JP2021528455A - Pyridine and pyrazine derivatives as preferred cannabinoid 2 agonists - Google Patents

Abstract

The present invention relates to a compound of formula (I), wherein A ¹ , A ² and R ^{1 to} R ⁵ are as defined in the specification and claims. The compound of formula (I) can be used as a cannabinoid 2 preferred agonist.

Description

The present invention relates to organic compounds useful in the treatment and / or prevention of mammals, in particular compounds that are preferential agonists of cannabinoid receptor 2.

（式中、
Ａ^１は、−ＣＨ−又は窒素であり；
Ａ^２は、−ＣＨ_２−又はカルボニルであり；
Ｒ^１は、ハロアルコキシアルキルシクロアルキル、ハロアルキルシクロアルキル、ハロアルコキシアルキル、ヒドロキシアルキルシクロアルキル、オキセタニル、ハロアルコキシアルキルオキセタニル、ヒドロキシアルキルオキセタニル、ハロアルキルオキセタニル、１−フルオロエチル、１−フルオロ−プロパ−２−イル、フルオロ−tert−ブチル、シクロプロピルフルオロメチル、フルオロシクロプロピル、ハロオキサニル、ハロテトラヒドロフラニル、フェニルアルコキシアルキルシクロアルキル、１−フルオロ−１，１−ジジューテロプロパ−２−イル、フルオロジジューテロメチル、フルオロジジューテロメチルオキシアルキルシクロアルキル、２−フルオロ−２，２−ジジューテロエチルオキシアルキルシクロアルキル、フルオロジジューテロメチルシクロアルキル、フルオロジジューテロメチルオキシアルキル、フルオロジジューテロメチルアルキル、フルオロジジューテロメチルオキシアルキルオキセタニル、２−フルオロ−２，２−ジジューテロエチルオキシアルキルオキセタニル、３−フルオロ−３，３−ジジューテロプロピルオキシアルキルオキセタニル、又はフルオロジジューテロメチルオキセタニルであり；
Ｒ^２は、アルコキシアゼチジニル、ハロアゼチジニル、ジハロアゼチジニル、ピロリジニル、又はアルキルフェニルスルホニルオキシアゼチジニルであり；
Ｒ^３及びＲ^４は、独立して、水素、アルキル、アルケニル、又はジューテロアルキルから選択され；
Ｒ^５は、水素、アルキル、ハロアルキル、ジュウテリオアルキル、アルキルフェニルスルホニルオキシアルキル、アルキルフェニルスルホニルオキシジューテロアルキル、又はヒドロキシアルキルであり；そして、
Ｘは、酸素又は−ＮＨ−である）
又はその薬学的に許容し得る塩に関する。 The present invention particularly relates to compounds of formula (I).

(During the ceremony,
A ¹ is -CH- or nitrogen;
A ² is -CH _2- or carbonyl;
R ¹ is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, haloalkoxyalkyl, hydroxyalkylcycloalkyl, oxetanyl, haloalkoxyalkyloxetanyl, hydroxyalkyloxetanyl, haloalkyloxetanyl, 1-fluoroethyl, 1-fluoro-propa-2- Il, fluoro-tert-butyl, cyclopropylfluoromethyl, fluorocyclopropyl, haloxanyl, halotetrahydrofuranyl, phenylalkoxyalkylcycloalkyl, 1-fluoro-1,1-dijuteropropa-2-yl, fluorodijutero Methyl, Fluorodiuteromethyloxyalkyl Cycloalkyl, 2-Fluoro-2,2-Dijuteroethyloxyalkylcycloalkyl, Fluorodiuteromethylcycloalkyl, Fluorodiuteromethyloxyalkyl, Fluorodiuteromethyl Alkyl, fluorodijuteromethyloxyalkyl oxetanyl, 2-fluoro-2,2-dijuteroethyloxyalkyl oxetanyl, 3-fluoro-3,3-dijuteropropyloxyalkyl oxetanyl, or fluorodijuteromethyloxetanyl Is;
R ² is alkoxy azetidinyloxyimino, Haroazechijiniru, dihalo azetidinyloxyimino, pyrrolidinyl, or an alkyl phenylsulfonyloxy azetidinyloxyimino;
R ³ and R ⁴ are independently selected from hydrogen, alkyl, alkenyl, or juteroalkyl;
R ⁵ is hydrogen, alkyl, haloalkyl, juuterioalkyl, alkylphenylsulfonyloxyalkyl, alkylphenylsulfonyloxyjuteroalkyl, or hydroxyalkyl; and
X is oxygen or -NH-)
Or the pharmaceutically acceptable salt thereof.

Compounds of formula (I) include, for example, pain, atherosclerosis, age-related yellow spot degeneration, diabetic retinopathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure. , Hepatic fibrosis, Pulmonary fibrosis, Renal fibrosis, Systemic fibrosis, Acute transplant rejection, Chronic transplant nephropathy, Diabetic nephropathy, Gloscular nephropathy, Myopathy, Heart failure, Myocardial ischemia, Myocardial infarction, Systemic sclerosis, burns, burns, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemia attacks, or vegetation inflammation It is especially useful in the treatment or prevention of diabetes.

Cannabinoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. Currently, two subtypes are known called cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are expressed primarily in the central nervous system (ie, amygdala, cerebellum, hippocampus) and in smaller amounts in the periphery. CB2 encoded by the CNR2 gene is mostly peripheral and is expressed in cells of the immune system such as macrophages and T cells (Non-Patent Documents 1 to 3) and in the gastrointestinal system (Non-Patent Document 4). The CB2 receptor is also widely distributed in the brain and is mainly found in microglia, but not in nerve cells (Non-Patent Document 5).

Interest in CB2 receptor agonists has steadily increased over the last decade (currently 30-40 patent applications per year), but some of the early development compounds are chronic pain (Non-Patent Document 6). ), Atherosclerosis (Non-Patent Document 7), Bone mass control (Non-Patent Document 8), Neuroinflammation (Non-Patent Document 9), Ischemic / reperfusion injury (Non-Patent Document 10), Systemic fiber This is due to the fact that it has been shown to have beneficial effects in preclinical models of a number of human diseases, including disease (Non-Patent Documents 11 and 12) and liver fibrosis (Non-Patent Documents 13 and 14). ..

Ischemia / reperfusion (I / R) injury is a major cause of tissue damage in conditions such as attacks, myocardial infarction, cardiopulmonary bypass and other vascular surgery, and organ transplantation, as well as various etiologies. It is also the main mechanism of terminal organ damage that exacerbates the process of circulatory shock. All of these conditions are characterized by disruption of the normal blood supply, resulting in inadequate oxygen supply to the tissues. Resupply of oxygen, such as reperfusion, is the final step in restoring normal oxygen supply to the tissue. However, if oxygen and nutrients are not supplied from the blood, even if the circulation is restored, further tissue damage will occur. The damage of reperfusion injury is partly due to the inflammatory response of the damaged tissue. White blood cells carried to the area by the newly recovered blood release many inflammatory factors, such as interleukins and free radicals, in response to tissue damage. The restored blood flow reintroduces oxygen into the cell, which damages cell proteins, DNA and cell membranes.

Remote ischemia preconditioning (RIPC) is a strategy that leverages the body's intrinsic defenses against injury caused by ischemia and reperfusion. It is an interesting phenomenon that transient non-fatal ischemia and reperfusion of an organ or tissue confer resistance to subsequent episodes of "fatal" ischemia-reperfusion injury in a distant organ or tissue. be. The actual mechanism by which protection is provided by transient ischemia and reperfusion of organs or tissues is currently unknown, but several hypotheses have been proposed.

The humoral hypothesis is that endogenous substances produced in distant organs or tissues (eg, adenosine, bradykinin, opioids, CGRP, endogenous cannabinoids, angiotensin I, or other humoral factors that have not yet been identified) flow through the bloodstream. It has been proposed that it invades and activates its respective receptors in target tissues, thereby restoring various intracellular pathways of cardiac protection involved in ischemic preconditioning.

Recent data indicate that endogenous cannabinoids and their receptors, especially CB2, may be involved in preconditioning and contribute to the suppression of reperfusion injury due to downregulation of the inflammatory response (). Non-Patent Document 10). Specifically, from recent studies using CB2 tool agonists, I in the heart (Non-Patent Document 15), brain (Non-Patent Document 16), liver (Non-Patent Document 17), and kidney (Non-Patent Document 18). The effectiveness of this concept has been demonstrated for the reduction of / R injuries.

In addition, over the last few years, there has been increasing literature showing that CB2 can also be of concern in subchronic and chronic situations. Specific upregulation of CB1 and CB2 is associated with proper expression of CB2 in myofibroblasts responsible for the progression of fibrosis in animal models of chronic diseases associated with fibrosis (Non-Patent Documents 12 and 19). It is shown that.

Activation of the CB2 receptor by a selective CB2 agonist has been shown to actually exert an antifibrotic effect in diffuse systemic sclerosis (Non-Patent Document 12), and the CB2 receptor is experimental. It has emerged as an important target in the pathophysiology of the liver, including fibrosis associated with cutaneous fibrosis (Non-Patent Document 11) and chronic liver disease (Non-Patent Documents 20-22).

Ashton, J.C. et al. Curr Neuropharmacol 2007, 5 (2), 73-80 Miller, A. M. et al. Br J Pharmacol 2008, 153 (2), 299-308 Centonze, D., et al. Curr Pharm Des 2008, 14 (23), 2370-42 Wright, K. L. et al. Br J Pharmacol 2008, 153 (2), 263-70 Cabral, G. A. et al. Br J Pharmacol 2008, 153 (2): 240-51 Beltramo, M. Mini Rev Med Chem 2009, 9 (1), 11-25 Mach, F. et al. J Neuroendocrinol 2008, 20 Suppl 1, 53-7 Bab, I. et al. Br J Pharmacol 2008, 153 (2), 182-8 Cabral, G. A. et al. J Leukoc Biol 2005, 78 (6), 1192-7 Pacher, P. et al. Br J Pharmacol 2008, 153 (2), 252-62 Akhmetshina, A. et al. Arthritis Rheum 2009, 60 (4), 1129-36 Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48 (9), 1050-6 Julien, B. et al. Gastroenterology 2005, 128 (3), 742-55 Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324 (2), 475-83 Defer, N. et al. Faseb J 2009, 23 (7), 2120-30 Zhang, M. et al. J Cereb Blood Flow Metab 2007, 27 (7), 1387-96 Batkai, S. et al. Faseb J 2007, 21 (8), 1788-800 Feizi, A. et al. Exp Toxicol Pathol 2008, 60 (4-5), 405-10 Yang, Y. Y. et al. Liver Int 2009, 29 (5), 678-85 Lotersztajn, S. et al. Gastroenterol Clin Biol 2007, 31 (3), 255-8 Mallat, A. et al. Expert Opin Ther Targets 2007, 11 (3), 403-9 Lotersztajn, S. et al. Br J Pharmacol 2008, 153 (2), 286-9

The compounds of the invention bind to and regulate the CB2 receptor and also have lower CB1 receptor activity.

As used herein, the term "alkyl", alone or in combination, is a straight chain or branched alkyl group having 1 to 8 carbon atoms, specifically a straight chain having 1 to 6 carbon atoms. Alternatively, an alkyl group of a branched chain, and more specifically, an alkyl group of a straight chain or a branched chain having 1 to 4 carbon atoms is shown. Examples of linear and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomer pentyl, isomer hexyl, isomer heptyl, and isomer octyl. Specifically, they are methyl, ethyl, propyl, butyl, and pentyl. Specific examples of alkyl are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl. Butyls such as methyl, ethyl, propyl, and isobutyl are specific examples of "alkyl" in the compounds of formula (I).

The term "cycloalkyl", alone or in combination, refers to a cycloalkyl ring having 3 to 8 carbon atoms, and specifically a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cycloheptyl, and cyclooctyl. A specific example of "cycloalkyl" is cyclopropyl.

The terms "alkoxy" or "alkyloxy", alone or in combination, are groups of the formula alkyl-O- (wherein the term "alkyl" has the meanings set forth above), such as methoxy, ethoxy, n. -Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy are shown. Specific examples of "alkoxy" are methoxy and ethoxy.

The term "oxy", alone or in combination, indicates an -O- group.

The term "halogen" or "halo", alone or in combination, refers to fluorine, chlorine, bromine, or iodine, and specifically fluorine, chlorine, or bromine, and more specifically fluorine. The term "halo", in combination with another group, refers to at least one halogen of the group, specifically 1 to 5 halogens, specifically 1 to 4 halogens, ie 1, 2 Indicates substitution by 3 or 4 halogens.

The term "haloalkyl", alone or in combination, is an alkyl substituted with at least one halogen, specifically 1-5 halogens, specifically 1-3 halogens. Indicates a group. Specific "haloalkyl" are fluoromethyl, fluoroethyl, fluoropropyl, and fluorobutyl.

The term "haloalkoxy", alone or in combination, is substituted with at least one halogen, specifically 1 to 5 halogens, specifically 1-3 halogens. Indicates an alkoxy group. Specific "haloalkoxy" are fluoromethoxy, fluoroethoxy, and fluoropropyloxy.

The terms "hydroxyl" and "hydroxy" indicate -OH groups alone or in combination.

The term "carbonyl", alone or in combination, indicates a -C (O) -group.

The term "amino", alone or in combination, refers to a primary amino group (-NH ₂ ), a secondary amino group (-NH-), or a tertiary amino group (-N-).

The term "aminocarbonyl" refers to _two -C (O) -NH groups, either alone or in combination.

The term "sulfonyl", alone or in combination, _{indicates a -SO 2} -group.

The term "pharmaceutically acceptable salt" refers to salts that retain biological effects and retain free base or free acid properties that are not biologically or otherwise undesirable. Point to. The salts are with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid, specifically hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid. , Maleic acid, malonic acid, succinic acid, fumaric acid, tartrate acid, citric acid, benzoic acid, silicate acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, formed with N-acetylcysteine Will be done. Moreover, these salts may be prepared by adding an inorganic base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium and magnesium. Salts derived from organic bases include primary, secondary and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine. , Triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, salts of polyamine resins, but not limited to these. The compound of formula (I) may be in the form of zwitterion. Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

It is well known in the art that one of the starting materials or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps. by applying the method, a suitable protecting group (e.g., "protective groups in Organic Chemistry" by TW Greene and PGM Wuts, 3 rd Ed., 1999, Wiley, protecting groups such as those described in New York) key It may be introduced before various steps. Such protecting groups can be removed in subsequent stages of synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl. (Moz).

The compound of formula (I) can contain several asymmetric centers and is an optically pure mirror isomer, such as a mixture of mirror isomers such as racemate, a mixture of diastereoisomers, It can exist in the form of a racemate of the diastereoisomer or a mixture of racemates of the diastereoisomer.

The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog rule, asymmetric carbon atoms can have an "R" or "S" configuration.

Therefore, the present invention relates to the following.

R ¹ is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, haloalkoxyalkyl, hydroxyalkylcycloalkyl, oxetanyl, haloalkoxyalkyloxetanyl, hydroxyalkyloxetanyl, haloalkyloxetanyl, 1-fluoroethyl, 1-fluoro-propa-2- Il, fluoro-tert-butyl, cyclopropylfluoromethyl, fluorocyclopropyl, haloxanyl, halotetrahydrofuranyl, 1-fluoro-1,1-dijuteropropa-2-yl, fluorodijoteromethyl, fluorodijutero Methyloxyalkylcycloalkyl, 2-fluoro-2,2-dijuteroethyloxyalkylcycloalkyl, fluorodijoteromethylcycloalkyl, fluorodijoteromethyloxyalkyl, fluorodijuteromethylalkyl, fluorodijotero Methyloxyalkyl oxetanyl, 2-fluoro-2,2-dijuteroethyloxyalkyl oxetanyl, 3-fluoro-3,3-dijuteropropyloxyalkyl oxetanyl, or fluorodijuteromethyloxetanyl; and
R ² is alkoxy azetidinyloxyimino, dihalo azetidinyloxyimino, or pyrrolidinyl, the compounds of the present invention.

A compound according to the present invention, wherein ^{A 1 is −CH−.}

A compound according to the present invention, wherein ^{A 2 is carbonyl.}

A compound according to the present invention, wherein ^{R 1 is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, or hydroxyalkylcycloalkyl.}

A compound according to the present invention, wherein ^{R 1 is hydroxyalkylcycloalkyl.}

A compound according to the present invention, wherein ^{R 1 is fluoromethoxymethylcyclopropyl, fluoromethylcyclopropyl, or hydroxymethylcyclopropyl.}

A compound according to the present invention, wherein ^{R 1 is hydroxymethylcyclopropyl.}

R ² is alkoxy azetidinyloxyimino or Haroazechijiniru, the compounds of the present invention.

R ² is alkoxy azetidinyloxyimino, the compounds of the present invention.

R ² is methoxy azetidinyloxyimino is Le or fluoro azetidinyloxyimino, the compounds of the present invention.

R ² is methoxy azetidinyloxyimino, the compounds of the present invention.

A ^{compound according to the present invention, wherein R 3} and R ⁴ are both alkyl at the same time or both are juterioalkyl at the same time.

A compound according to the present invention, wherein both ^{R 3} and R ^{4 are alkyl at the same time.}

A ^{compound according to the present invention, wherein R 3} and R ⁴ are both ethyl at the same time or both are juuterioethyl at the same time.

A compound according to the present invention, wherein both ^{R 3} and R ^{4 are ethyl at the same time.}

R ⁵ is alkyl, haloalkyl, or halo Jewelery is Theriault alkyl, the compounds of the present invention.

R ⁵ is a haloalkyl or halo Jewelery Theriault alkyl, the compounds of the present invention.

R ⁵ is ethyl, fluoromethyl, fluoropropyl, fluorobutyl, or fluoro hexadeuteriodimethylsulfoxide Theriault propyl, the compounds of the present invention.

R ⁵ is a fluoropropyl or fluoro hexadeuteriodimethylsulfoxide Theriault propyl, the compounds of the present invention.

A compound according to the present invention, wherein X is oxygen.

Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-) 1-yl) pyridine-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-({6- [3- (fluoromethoxy) -2,2-dimethylpropoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
(+)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart;
(-)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoateethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine) -1-yl) pyridin-2-carbonyl] amino} butanoate;
(-)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carbonyl] amino} butanoate;
(+)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
(+)-Trans-2-fluoroethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart;
(-)-Trans-2-fluoroethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3) -Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
Fluoromethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
2-Fluoroethyl 2-Ethyl-2-{[6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3) -Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
Fluoromethyl 2-ethyl-2-({5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carbonyl} amino) butanoate;
2-Fluoroethyl 2-Ethyl-2-({5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carbonyl} amino) butanoate;
3-Fluoropropyl 2-ethyl-2-({5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carbonyl} amino) butanoate;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2- Carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine- 2-Carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine- 2-Carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine -2-Carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy ] Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy ] Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) Methoxy] Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) Methoxy] Pyridine-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carboxamide ;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine-2 -Carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine-2 -Carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-[(oxetane-3-yl) methoxy] -5- (pyrrolidin-1-yl) pyridine- 2-Carboxamide;
Ethyl 2-ethyl-2-{[6-({3-[(fluoromethoxy) methyl] oxetane-3-yl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-({3-[(2-fluoroethoxy) methyl] oxetane-3-yl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({3-[(3-fluoropropoxy) methyl] oxetane-3-yl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
Fluoromethyl 2-ethyl-2-{[6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} Butano art;
2-Fluoroethyl 2-Ethyl-2-{[6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) Il) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazeti) Din-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carboxamide;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3) -Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-({(1S, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-({(1S, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-{[(1S, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5- (3- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-({(1R, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-({(1R, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
6-({3-[(fluoromethoxy) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine-1-) Il) Pyridine-2-carboxamide;
6-({3-[(2-fluoroethoxy) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
6-({3-[(3-Fluoropropoxy) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
6-{[3- (fluoromethyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine-1-yl) pyridine -2-Carboxamide;
6-({3-[(fluoromethoxy) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carboxamide;
6-({3-[(2-fluoroethoxy) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
6-({3-[(3-Fluoropropoxy) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
6-{[3- (fluoromethyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1-yl) pyridine- 2-Carboxamide;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyrazine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyrazine-2 −carbonyl] amino} butanoart;
6-({(1S, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-Methoxyazetidine-1-yl) pyrazine-2-carboxamide;
6-({(1R, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5-( 3-Methoxyazetidine-1-yl) pyrazine-2-carboxamide;
Ethyl 2-ethyl-2-({6-[(3-fluorooxane-4-yl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
1,4-Anhydro-2,3-dideoxy-5-O- [6-{[3- (ethoxycarbonyl) pentane-3-yl] carbamoyl} -3- (3-methoxyazetidine-1-yl) pyridine -2-yl] -2-fluoropentitol;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[2-fluoro (2,2-dijuuterio) ethyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate ;
Ethyl 2-ethyl-2-({6-[(3-fluorooxane-4-yl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
1,4-Anhydro-2,3-dideoxy-5-O- [6-{[3- (ethoxycarbonyl) pentane-3-yl] carbamoyl} -3- (3-methoxyazetidine-1-yl) pyridine -2-yl] -2-fluoropentitol;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2-({[2-fluoro (2,2-2-2H_2_) ethyl] oxy} methyl) cyclopropyl] methoxy} -5 -(3-Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2- [fluoro (dijuuterio) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2- [fluoro (dijuuterio) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2-({[2-fluoro (2,2-dijuuterio) ethyl] oxy} methyl) cyclopropyl] methoxy} -5- (3) -Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6-(3-{[fluoro (dijuuterio) methyl] oxy} -2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2,2-dimethyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2R) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[2-fluoro (2,2-dijuuterio) ethyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate ;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[2-fluoro (2,2-dijuuterio) ethyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate ;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
6-{[3-({[fluoro (dijuuterio) methyl] oxy} methyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3- (3-) Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-{[3-({[2-fluoro (2,2-dijuuterio) ethyl] oxy} methyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-{[3-({[3-Fluoro (3,3-dijuuterio) propyl] oxy} methyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-({3- [fluoro (dijuuterio) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine-1-yl) Il) Pyridine-2-carboxamide;
6-{[3-({[fluoro (dijuuterio) methyl] oxy} methyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
6-{[3-({[2-fluoro (2,2-dijuuterio) ethyl] oxy} methyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl]- 5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-{[3-({[3-Fluoro (3,3-dijuuterio) propyl] oxy} methyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl]- 5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-({3- [fluoro (dijuuterio) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carboxamide;
3-Fluoropropyl-3,4-dijuuterio-2- (1,2-dijuuterioethyl) -2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy]- 5- (3-Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
Fluoromethyl-2-ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate;
2-Fluoroethyl-2-ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate;
3-Fluoropropyl-2-ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate;
(1,1,2,2,3,3-Hexajuterio-3-fluoro-propyl) 2-Ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl]] Methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
3-Fluoropropyl 2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino ] -2-Vinyl-Buta-3-Enoart;
3-Fluoropropyl 3,4-dijuuterio-2- (1,2-dijuuterioethyl) -2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5] -(3-Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
(Rac) -trans-3-fluoropropyl 2-[[6-[[(1S, 2S) -2- (benzyloxymethyl) cyclopropyl] methoxy] -5- (3-hydroxyazetidine-1-yl) Pyridine-2-carbonyl] amino] -2-ethyl-butanoate;
3- (p-Tolylsulfonyloxy) propyl 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino] Butanoart;
[1,1,2,2,3,3-hexajuuterio-3- (p-tolylsulfonyloxy) propyl] 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxy) Methyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
4-Fluorobutyl 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino] butanoart;
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -6-[[(1S, 2S) -2- (hydroxymethyl) cyclo Propyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridine-2-carboxamide;
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6- [ [(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridine-2-carboxamide;
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6- [ [(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridine-2-carboxamide;
3-Fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} pyridine-2 -Il] formamide} butanoart;
3-Fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} pyridine-2 -Il] formamide} butanoart;
(Rac) -trans-3-fluoropropyl 2-ethyl-2-[[6-[[-2- (hydroxymethyl) cyclopropyl] methoxy] -5- [3- (p-tolylsulfonyloxy) azetidine-1 -Il] Pyridine-2-carbonyl] Amino] Butanoart;
3-Fluoropropyl 2-[[6-[[(1S, 2S) -2- (benzyloxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino] -2-ethyl-butanoart;
Ethyl 2-ethyl-2-{[6- (2-fluoropropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-({6-[(1-fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
Ethyl 2-ethyl-2-({6-[(2-fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
Ethyl 2-ethyl-2-{[6- (2-fluoropropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-({6-[(1-fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate; and ethyl 2-ethyl -2-({6-[(2-Fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
A compound according to the present invention or a pharmaceutically acceptable salt thereof, which is selected from the above.

Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
(+)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart;
(+)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino} butanoate; and 3-fluoropropyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine) A compound according to the present invention, or a pharmaceutically acceptable salt thereof, selected from -1-yl) pyridine-2-carbonyl] amino} butanoate.

The present invention further relates, in particular, 3-fluoropropyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine). -1-Il) Pyridine-2-carbonyl] Amino} butanoate.

The present invention also relates, in particular, (1,1,2,2,3,3-hexajuuterio-3-fluoro-propyl) 2-ethyl-2-[[6-[[(1S, 2S) -2). -(Hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate.

Synthesis of the compound of formula (I) can be achieved, for example, according to the following scheme.

According to the procedure according to Scheme 1, compound AA (A ¹ = CH, R'= H, methyl, ethyl, isopropyl, tert-butyl, or, for example, TW Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New york 1999, 3 ^rd edition another suitable protecting group) that is described in can be used as starting materials. AA can be commercially available, described in the literature, or synthesized by one of ordinary skill in the art.

Compound AB can be prepared from AA by oxidizing with a suitable oxidizing reagent under conditions known to those skilled in the art (step a), eg, by treating with 3-chloroperbenzoic acid in dichloromethane at ambient temperature. can.

For example, by treating with trichloride or phosphoryl tribromide at temperatures from 20 ° C. to the boiling point of the solvent, without additional solvent or in a suitable solvent such as chloroform, or using other conditions known in the literature. By doing so, the compound AB can be converted to 6-chloro or 6-bromo-picoline AC (X = Cl, Br) (step b).

Suitable for cyclopropylmethanol and the like in the presence of bases such as sodium hydride, with or without the use of inert solvents such as dimethylformamide, at temperatures in the range of room temperature to the reflux temperature of the solvent, especially at room temperature. By reacting with the substituted primary or secondary alcohol AD, 6-chloro- or bromo-picoline AC (X = Cl, Br) can be converted to compound AE (step c).

By a method well known to those skilled in the art, the general formula AE (R') is used at temperatures from 0 ° C. to the reflux temperature of the solvent used, eg, tetrahydrofuran / ethanol or another suitable solvent-in aqueous LiOH, NaOH, or KOH. The ester of ≠ H) is saponified to the acid of General Formula II (step d).

A suitable amide bond forming reaction can prepare compound I from the corresponding amines of formula II and formula III (step e). These reactions are known in the art. For example, N, N'-carbonyl-diimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimidehydrochloride (EDCI), 1- [bis (Dimethylamino) -methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole ( HOBT), O-benzotriazole-1-yl-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N, N, N', N'- Such conversions can be made using coupling reagents such as tetramethyl-uronium-hexafluoro-phosphate (HBTU). A simple method is to use HBTU and a base such as N-methylmorpholine in an inert solvent such as dimethylformamide at room temperature, for example.

Alternatively, compound AC (R '= methyl, ethyl, isopropyl, tert-butyl, or e.g., TW Greene et al., Is described in Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd edition Another suitable protective group) is i) converted to its acid homologous AC (R'= H) as described in step d; ii) treated by treatment with amine III as described in step e. And iii) can be reacted with alcohol AD to reach compound I as described in step c.

Amine III and alcohol AD can be commercially available, described in the literature, synthesized by one of ordinary skill in the art, or synthesized as described in the experimental section.

If one of the starting materials, compounds of formula AA, AD, or III contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, the present invention. by applying methods well known in the art, suitable protecting groups (P) (e.g., TW Greene et al., is described in protective groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd edition Such) may be introduced before important steps. Such protecting groups can be removed in subsequent stages of synthesis using standard methods known in the art.

If one or more compounds of formulas AA-AE, AD, II, or III contain a chiral center, the picoline of formula I can be obtained as a mixture of diastereomers or enantiomers. , (Chiral) HPLC or crystallization and the like can be separated by methods well known in the art. Racemic compounds are counterpodeal via diastereomeric salts, for example, by crystallizing or by separating the antipode by a specific chromatography method using either a chiral adsorbent or a chiral eluent. Can be separated into the body.

According to the procedure according to Scheme 2, compound BA (A ¹ = CH, R'= H, methyl, ethyl, isopropyl, tert-butyl, or, for example, TW Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New york 1999, 3 ^rd edition another suitable protecting group) that is described in can be used as starting materials. BA is commercially available (eg, for R'= methyl: 5-bromo-6-chloro-pyridin-2-carboxylic acid methyl ester, CAN 1214353-79-3), described in the literature, or Can be synthesized by one of ordinary skill in the art.

Palladium catalysts such as tris (dibenzylideneacetone) dipalladium / dimethylbisdiphenyl-phosphinoxanthene and carbonic acid in a solvent such as 1,4-dioxane, preferentially at the boiling point of the solvent, by methods well known to those skilled in the art. Compound AC'can be prepared from BA by coupling with amine BB (M is H) using a base such as cesium (step a).

Compound AC'is further i) reacted with compound AD to form compound AE as described in step c of scheme 1; ii) saponified as described in step d of scheme 1; and iii). Compound I can be produced by forming an amide bond as described in step e of Scheme 1.

Further, as described in step c of Scheme 1, compound BA can be converted to compound BC by treating with compound AD (step d).

Subsequently, as discussed in the conversion of BA to AC', compound BC can be converted to compound AE (step a).

Compound AE can further produce compound I by saponifying i) as described in step d of scheme 1; ii) forming an amide bond as described in step e of scheme 1.

Alternatively, the compound BC (R '= methyl, ethyl, isopropyl, tert-butyl, or e.g., TW Greene et al., Is described in Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd edition Another suitable protective group) is i) converted to its acid homologous BC (R'= H) as described in step d of scheme 1; ii) amine III as described in step e of scheme 1. It can be converted to the corresponding amide by treatment with; and iii) react with BB as described in step a to reach compound I.

In addition, Compound I can also be synthesized by applying the following reaction sequence: i) Compound BA (R'= methyl, ethyl, isopropyl, tert-butyl, or, for example, TW, as described in step d of Scheme 1. Greene et al., protective groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd edition saponified to another suitable protecting group) as described in, its acid homologs BA (R '= H) and ii) converted to the corresponding amide by treatment with amine III as described in step e of scheme 1; iii) reacted with compound BB as described in step a; and iv) step. As described in b, it is reacted with compound AD. In some cases, steps iii) and iv) may be interchangeable.

If one of the starting materials, compounds of formula BA, BB, AD, or III contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps. by applying methods well known in the art, suitable protecting groups (P) (e.g., TW Greene et al., is described in protective groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd edition May be introduced before important steps. Such protecting groups can be removed in subsequent stages of synthesis using standard methods known in the art.

If one or more compounds of formula BA, BB, AD, or III contain a chiral center, the picoline of formula AC', AE, BC, BD, and I is a mixture of diastereomers or enantiomers. It can be separated by methods well known in the art such as (chiral) HPLC or crystallization. Racemic compounds are counterpodeal via diastereomeric salts, for example, by crystallizing or by separating the antipode by a specific chromatography method using either a chiral adsorbent or a chiral eluent. Can be separated into the body.

Following the procedure according to Scheme 3, compound CA (R '= H, methyl, ethyl, isopropyl, tert-butyl, or e.g. TW Greene et al., Protective Groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd Another suitable protecting group described in the edition) can be used as a starting material. CA is commercially available (eg, for R'= methyl: 5-chloro-pyrazine-2-carboxylic acid methyl ester, CAN 33332-25-1), described in the literature, or synthesized by one of ordinary skill in the art. Can be done.

By coupling with an amine BB (M is H) by a method well known to those skilled in the art, for example, at a temperature in the range of room temperature to 45 ° C., in the presence of an inert solvent, especially dioxane, a base, especially triethylamine. Then, the compound CB can be prepared from CA by reacting with the corresponding amine BB (M is H) (step a).

Compounds by electrophilic aromatic bromination in a suitable solvent, especially by bromination with N-bromosuccinimide in chloroform at high temperatures, especially at 60 ° C., or by using other conditions known in the literature. CB can be converted to CC (step b).

Esters of the general formula CC are prepared by methods well known to those skilled in the art, from 0 ° C. to the reflux temperature of the solvent used, eg, using tetrahydrofuran / ethanol or another suitable solvent-in aqueous LiOH, NaOH, or KOH. It is saponified to the acid of the general formula CD (step c).

Suitable for substituted cyclopropylmethanol, etc., in the presence of a base such as potassium hydroxide, at a temperature in the range of room temperature to the reflux temperature of the solvent, especially at room temperature, with or without the use of an inert solvent such as DMSO. By reacting with the substituted primary or secondary alcohol AD, the bromo-pyrazine CD can be converted to compound CE (step d).

A suitable amide bond-forming reaction can prepare compound I from the acid CE and the corresponding amine of formula III (step e). These reactions are known in the art. For example, N, N'-carbonyl-diimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimidehydrochloride (EDCI), 1- [bis (Dimethylamino) -methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole ( HOBT), O-benzotriazole-1-yl-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU), and O-benzotriazole-N, N, N', N'- Such conversions can be made using coupling reagents such as tetramethyl-uronium-hexafluoro-phosphate (HBTU). A simple method is to use HBTU and a base such as N-methylmorpholine in an inert solvent such as dimethylformamide at room temperature, for example.

Amine III and alcohol AD can be commercially available, described in the literature, synthesized by one of ordinary skill in the art, or synthesized as described in the experimental section.

If one of the starting materials, compounds of formula CA, BB, AD, or III contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps. by applying methods well known in the art, suitable protecting groups (P) (e.g., TW Greene et al., is described in protective groups in Organic Chemistry, John Wiley and Sons Inc. New York 1999, 3 rd edition May be introduced before important steps. Such protecting groups can be removed in subsequent stages of synthesis using standard methods known in the art.

If one or more compounds of formula CA, BB, AD, or III contain a chiral center, the pyrazines of formulas CB-CE or I can be obtained as a mixture of diastereomers or enantiomers. It can be separated by methods well known in the art such as (chiral) HPLC or crystallization. Racemic compounds are counterpodeal via diastereomeric salts, for example, by crystallizing or by separating the antipode by a specific chromatography method using either a chiral adsorbent or a chiral eluent. Can be separated into the body.

を式（A2）の化合物

と、カップリング剤及び塩基の存在下で反応させる工程；
（ｂ）式（Ｂ）の化合物

を、Ｒ^２Ｍ、パラジウム触媒、及び塩基の存在下で反応させる工程；
（式中、Ａ^１、Ａ^２、Ｒ^１〜Ｒ^５、及びＸは、上に定義したとおりであり、そして、Ｙは、ハロゲンである）。 Therefore, the present invention also relates to a process for preparing a compound according to the present invention, which comprises one of the following steps:
(A) Compound of formula (A1)

The compound of formula (A2)

And the step of reacting in the presence of a coupling agent and a base;
(B) Compound of formula (B)

A step of reacting in the presence of R 2 ^M, a palladium catalyst, and a base;
(In the equation, A ¹ , A ² , R ^{1 to} R ⁵ , and X are as defined above, and Y is a halogen).

The coupling agent in step (a) may simply be, for example, N, N'-carbonyl-diimidazole (CDI), N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl)-. 3-Ethylcarbodiimidehydrochloride (EDCI), 1- [bis (dimethylamino) -methylene] -1H-1,2,3-triazoro [4,5-b] pyridinium-3-oxide hexafluorophosphate (HATU) , 1-Hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazole-1-yl-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU), or It is an amide bond forming agent such as O-benzotriazole-N, N, N', N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU).

N-methylmorpholine is a convenient base for step (a).

HBTU may advantageously be used in combination with N-methylmorpholine in step (a).

The solvent in step (a) may advantageously be dimethylformamide.

In step (b), the palladium catalyst may be, for example, tris (dibenzylideneacetone) dipalladium / dimethylbisdiphenyl-phosphinoxanthene.

In step (b), the base may be, for example, cesium carbonate.

In step (b), the solvent is advantageously 1,4-dioxane.

Y may be bromine for convenience.

The present invention also relates to a compound according to the present invention when produced according to the process of the present invention.

Another embodiment of the invention comprises a pharmaceutical composition or medicament containing the compound of the invention and a therapeutically inert carrier, diluent, or excipient, and such compositions and formulations. Provided are methods of using the compounds of the invention for preparation. In one example, the compound of formula (I) is non-toxic to the recipient at ambient temperature, suitable pH, and desired purity, a physiologically acceptable carrier, ie, the dosage and concentration used. It can be formulated into a galenus dosage form by mixing with a carrier. The pH of the pharmaceutical product depends mainly on the specific use and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer of pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

The composition is formulated, dispensed, and administered to meet good medical practice. Factors to consider in this situation include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the drug, the method of administration, the schedule of administration, and the physician. Includes other known factors.

The compounds of the present invention can be oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural. It may be administered by any suitable means, including external and intranasal and, if topical treatment is desired, intralesional administration. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compound of the present invention is administered in any simple administration form, for example, tablets, powders, capsules, liquids, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. You can do it. Such compositions may contain components commonly used in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents, and additional activators.

A typical preparation is prepared by mixing a compound of the present invention with a carrier or an excipient. Suitable carriers and excipients are well known to those of skill in the art and, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Philadelphia: Lippincott, Williams & Wilkins, 2004 Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Has been done. The preparation also comprises one or more buffers, stabilizers, to make the drug (ie, the compound of the invention or a pharmaceutical composition thereof) look beautiful or to support the production of the drug (ie, the drug). , Surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow promoters, processing aids, colorants, sweeteners, fragrances, It may contain flavoring agents, diluents, and other known additives.

Further, the present invention particularly relates to the following.

Pain, atherosclerosis, age-related yellow spot degeneration, diabetic nephropathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, myocardial disease, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening Compounds of formula (I) for treating or preventing sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation. Use of.

Pain, atherosclerosis, age-related yellow spot degeneration, diabetic nephropathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, myocardial disease, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening To prepare drugs for treating or preventing sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation, Use of the compound of formula (I).

Pain, atherosclerosis, age-related yellow spot degeneration, diabetic nephropathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, myocardial disease, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening Formula (I) for use in the treatment or prevention of sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation. Compound. and,

Pain, atherosclerosis, age-related yellow spot degeneration, diabetic nephropathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, myocardial disease, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening A method for treating or preventing sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation, and an effective amount formula. A method comprising administering the compound of (I) to a patient in need thereof.

The present invention relates in particular to compounds of formula (I) for treating or preventing ischemia, reperfusion injury, cirrhosis, or liver tumors, specifically ischemia or reperfusion injury.

The present invention is illustrated by the following examples, but these are not limited.

Abbreviation AcOH- = acetic acid; rac-BINAP = racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl); CAN = CAS number; DCM = dichloromethane; DEA = diethanolamine; DIPEA = N-ethyl- N-isopropylpropan-2-amine; DMF = dimethylformamide; DPPA = diphenylphosphoryl azide; EDC = 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; EI = electron shock; EtOAc = ethyl acetate; HATU = 2 -(3H- [1,2,3] triazolo [4,5-b] pyridine-3-yl) -1,1,3,3-tetramethylisouronium hexafluorophosphate (V); HBTU = O -Benzotriazole-N, N, N', N'-tetramethyl-uronium-hexafluoro-phosphate; THF = hydroxybenzotriazole; HPLC = LC = high performance liquid chromatography; ISP = ion spray, ESI (electrospray) Corresponding; LAH = Lithium Marminium Hydrochloride; LC = Liquid Chromatography; LiTMP = Lithium Tetramethyl Piperidine; MS = Mass Analysis; NMR data reported at one-millionth (δ) relative to internal tetramethylsilane Based on the heavy hydrogen lock signal from the sample solvent (d _6- DMSO unless otherwise noted); the binding constant (J) is Hertz; m-CPBA = meta-chloroperoxybenzo. Acid; mp = melting point; PTSA = p-toluenesulfonic acid; RT = room temperature; Rt = retention time; SFC = supercritical fluid chromatography; SOR = specific luminosity; TBAF = tetra-n-butylammonium fluoride; TBTU = O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyl-uronium-tetrafluoroborate; THF = tetrahydrofuran.

Example 1
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-) 1-yl) pyridine-2-carbonyl] amino} butanoart

２５０mLの丸底フラスコ中で、鉱油中水素化ナトリウム（５０７mg、１２．７mmol、当量：２）を、ＤＭＦ（５０mL）と合わせて灰色の懸濁液を得、これを０℃に冷却した。（Rac）−trans−（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メタノール（２．０６ｇ、９．５２mmol、当量：１．５）をＤＭＦ（１００mL）に溶解し、反応混合物に加え、これを０℃で１時間撹拌した。５−ブロモ−６−クロロピコリン酸（ＣＡＮ ９５９９５８−２５−９、１５００mg、６．３４mmol、当量：１）をＤＭＦ（２０mL）に溶解し、反応混合物に加えた。撹拌を室温で２０時間続けた。水素化ナトリウム（２５０mg）を加え、撹拌を３時間続けた。別の部分のＮａＨ（４５０mg）及び（rac）−trans−（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メタノール（３００mg）を加えた。室温で３時間撹拌した後、反応混合物を水の添加によりクエンチし、そして真空中で濃縮した。残留物を、ＨＣｌ（１Ｍ）の添加により注意深く酸性化した。混合物をＥｔＯＡｃで希釈し、ブライン（３×２５０mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮して無色の油状物になった。粗生成物を、カラムクロマトグラフィー（ＳｉＯ_２、５０ｇ、ｈｅｐｔ．／ＥｔＯＡｃ）により精製して、濃縮された標記化合物（１ｇ）を得、これは次の工程で実施するのに十分に純粋であった、ＭＳ（ＩＳＰ）：４１６．３ ［ＭＨ^＋］。 a) (Rac) -trans-5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) picolinic acid

Sodium hydride in mineral oil (507 mg, 12.7 mmol, equivalent: 2) was combined with DMF (50 mL) to give a gray suspension in a 250 mL round bottom flask, which was cooled to 0 ° C. Dissolve (Rac) -trans- (-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methanol (2.06 g, 9.52 mmol, equivalent: 1.5) in DMF (100 mL). , The reaction mixture was added and this was stirred at 0 ° C. for 1 hour. 5-Bromo-6-chloropicolinic acid (CAN 959958-25-9, 1500 mg, 6.34 mmol, equivalent: 1) was dissolved in DMF (20 mL) and added to the reaction mixture. Stirring was continued at room temperature for 20 hours. Sodium hydride (250 mg) was added and stirring was continued for 3 hours. Another portion of NaH (450 mg) and (rac) -trans- (-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methanol (300 mg) was added. After stirring at room temperature for 3 hours, the reaction mixture was quenched by the addition of water and concentrated in vacuo. The residue was carefully acidified by the addition of HCl (1M). The mixture was diluted with EtOAc and washed with brine (3 x 250 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo to give a colorless oil. The crude product was purified by column chromatography (SiO _2, 50 g, hept./ EtOAc) to give the concentrated title compound (1 g), which was pure enough to be carried out in the next step. Also, MS (ISP): 416.3 [MH ⁺ ].

５０mLの丸底フラスコ中で、（rac）−trans−５−ブロモ−６−（（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メトキシ）ピコリン酸（１．０２ｇ、２．４５mmol、当量：１．５）を、ＤＭＦ（２８．２mL）と合わせて無色の溶液を得た。ＤＩＰＥＡ（１．０６ｇ、１．４３mL、８．１８mmol、当量：５）及びＴＢＴＵ（７８８mg、２．４５mmol、当量：１．５）を加えた。エチル ２−アミノ−２−エチルブタノアート塩酸塩（ＣＡＮ １１３５２１９−２９−２、３２０mg、１．６４mmol、当量：１）を加え、反応混合物を室温で１時間撹拌した。溶媒を減圧下で除去し、残留物をＥｔＯＡｃに溶解した。有機層を合わせ、飽和ＮａＨＣＯ_３（３×２０mL）、１Ｍ ＨＣｌ（３×２０mL）、及び飽和ＮａＣｌ（３×２０mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮した。粗生成物を、カラムクロマトグラフィー（ＳｉＯ_２、５０ｇ、ｈｅｐｔ．／ＥｔＯＡｃ）により精製して、標記化合物（２３５mg、２６％）を無色の油状物として得た、ＭＳ（ＩＳＰ）：５５６．８ ［Ｍ−Ｈ⁻］。 b) (Rac) -trans-ethyl 2- (5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) picoline amide) -2-ethylbutano art

In a 50 mL round bottom flask, (rac) -trans-5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) picolinic acid (1.02 g, 2.45 mmol, equivalent: 1.5) was combined with DMF (28.2 mL) to give a colorless solution. DIPEA (1.06 g, 1.43 mL, 8.18 mmol, equivalent: 5) and TBTU (788 mg, 2.45 mmol, equivalent: 1.5) were added. Ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2, 320 mg, 1.64 mmol, equivalent: 1) was added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layers were combined and washed with _{saturated NaCl 3} (3 x 20 mL), 1M HCl (3 x 20 mL), and saturated NaCl (3 x 20 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , 50 g, hept./ EtOAc) to give the title compound (235 mg, 26%) as a colorless oil, MS (ISP): 556.8 [ ^M-H -].

２０mLの密封管中で、（rac）−trans−エチル ２−（５−ブロモ−６−（（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メトキシ）ピコリンアミド）−２−エチルブタノアート（２２８mg、４０９μmol、当量：１）を、トルエン（１５mL）と合わせて無色の溶液を得た。Ｃｓ_２ＣＯ_３（４００mg、１．２３mmol、当量：３）及び３−メトキシアゼチジン塩酸塩（ＣＡＮ １４８６４４−０９−１、７５．５mg、６１３μmol、当量：１．５）を加えた。rac−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル（５０．９mg、８１．８μmol、当量：０．２）及びパラジウム（II）アセタート（１８．４mg、８１．８μmol、当量：０．２）を加えた。反応混合物を１１０℃で４時間撹拌し、ＥｔＯＡｃで希釈し、そしてセライトに通して濾過した。有機溶媒を減圧下で除去し、残留物をＥｔＯＡｃに溶解した。有機層を合わせ、１Ｍ ＨＣｌ（３×２５mL）及び飽和ＮａＣｌ（１×２５mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮した。粗生成物を、カラムクロマトグラフィー（ＳｉＯ_２、２０ｇ、ｈｅｐｔ．／ＥｔＯＡｃ）により精製して、標記化合物（２０７mg、９０％）を無色の油状物として得た。 c) (Rac) -trans-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) ) Picoline amide) -2-ethylbutanoart

In a 20 mL sealed tube, (rac) -trans-ethyl 2- (5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) picoline amide)- 2-Ethylbutanoate (228 mg, 409 μmol, equivalent: 1) was combined with toluene (15 mL) to give a colorless solution. Cs ₂ CO ₃ (400 mg, 1.23 mmol, equivalent: 3) and 3-methoxyazetidine hydrochloride (CAN 148644-09-1, 75.5 mg, 613 μmol, equivalent: 1.5) were added. rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (50.9 mg, 81.8 μmol, equivalent: 0.2) and palladium (II) acetate (18.4 mg, 81.8 μmol, Equivalent: 0.2) was added. The reaction mixture was stirred at 110 ° C. for 4 hours, diluted with EtOAc and filtered through Celite. The organic solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layers were combined and washed with 1M HCl (3 x 25 mL) and saturated NaCl (1 x 25 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , 20 g, hept./ EtOAc) to give the title compound (207 mg, 90%) as a colorless oil.

５０mLの丸底フラスコ中で、（rac）−trans−エチル ２−（６−（（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）−２−エチルブタノアート（２００mg、３５５μmol、当量：１）を、ＡｃＯＨ（３mL）、水（１mL）及びＴＨＦ（１mL）と合わせて、無色の溶液を得た。反応混合物を室温で１時間撹拌した。有機溶媒を減圧下で除去し、残留物をＥｔＯＡｃで希釈した。有機層を合わせ、飽和ＮａＨＣＯ_３（３×１０mL）及び飽和ＮａＣｌ（１×２５mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮して、標記化合物（１８６mg、定量）を無色の油状物として得、これを更に精製することなく次の工程で用いた、ＭＳ（ＩＳＰ）：４５０．３４３ ［ＭＨ^＋］。 d) (Rac) -trans-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoate

In a 50 mL round bottom flask, (rac) -trans-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) -5- (3-methoxy) Azetidine-1-yl) picoline amide) -2-ethylbutanoate (200 mg, 355 μmol, equivalent: 1) was combined with AcOH (3 mL), water (1 mL) and THF (1 mL) to form a colorless solution. Obtained. The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was removed under reduced pressure and the residue was diluted with EtOAc. The organic layers were combined and washed with _{saturated NaCl 3} (3 x 10 mL) and saturated NaCl (1 x 25 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo to give the title compound (186 mg, quantitative) as a colorless oil which was used in the next step without further purification, MS (ISP). ): 450.343 [MH ⁺ ].

e) Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazeti) Din-1-yl) pyridine-2-carbonyl] amino} butanoate In a 5 mL round bottom flask, (rac) -trans-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) ) Methoxy) -5- (3-methoxyazetidine-1-yl) picolinamide) butanoate (31 mg, 69 μmol, equivalent: 1) was combined with DMF (1 mL) to obtain a pale yellow solution. Sodium hydride (13.8 mg, 345 μmol, equivalent: 5) on the mineral oil was added and the reaction mixture was stirred at room temperature for 30 minutes. Fluoroiodo-methane (55.1 mg, 23.3 μL, 345 μmol, equivalent: 5) was added. The reaction mixture was stirred at room temperature for 12 hours, diluted with EtOAc and washed with brine (3 x 10 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo to give the title compound (2.5 mg, 5.19 μmol, 8%) as a colorless oil, MS (ISP): 482.370 [ MH ⁺ ].

実施例１ｅに記載した手順と同様にして、（rac）−trans−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例１ｄ）をフルオロ−ヨード−エタンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＩＳＰ）：４９２．３５９ ［ＭＨ^＋］。 Example 2
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate

Similar to the procedure described in Example 1e, (rac) -trans-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazeti). Din-1-yl) picoline amide) butanoate (Example 1d) was reacted with fluoro-iodo-ethane to give the title compound as a colorless oil, MS (ISP): 492.359 [MH ⁺ ].

Example 3
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} butanoate and ethyl 2-ethyl-2-{[6-{[(1R, R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart

５mLの丸底フラスコ中で、（rac）−trans−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例１ｄ、５０mg、１１１μmol、当量：１）を、ＣＨ_２Ｃｌ_２（１０００μL）と合わせて、無色の溶液を得た。反応混合物を０℃に冷却し、トリエチルアミン（３３．８mg、４６．５μL、３３４μmol、当量：３）及び塩化メタンスルホニル（２５．５mg、１７．３μL、２２２μmol、当量：２）を加えた。反応混合物を室温で２時間撹拌した。更なる１０uLの塩化メタンスルホニルを加え、撹拌を３０分間続けた。反応混合物をＥｔＯＡｃで希釈し、有機層を１Ｍ ＨＣｌ（３×１０mL）、飽和ＮａＨＣＯ_３（３×１０mL）、及び飽和ＮａＣｌ（１×２０mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮して、粗標記化合物を得、これを更に精製することなく次の工程で用いた、ＬＣ−ＭＳ：５２８．３ ［ＭＨ^＋］。 a) (Rac) -trans-ethyl 2-ethyl-2- (5- (3-methoxyazetidine-1-yl) -6-((-2-(((methylsulfonyl) oxy) methyl) cyclopropyl)) Methoxy) picoline amide) butanoart

In a 5 mL round bottom flask, (rac) -trans-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-) Il) picoline amide) butanoate (Example 1d, 50 mg, 111 μmol, equivalent: 1) was _{combined with CH 2} Cl ₂ (1000 μL) to obtain a colorless solution. The reaction mixture was cooled to 0 ° C. and triethylamine (33.8 mg, 46.5 μL, 334 μmol, equivalent: 3) and methanesulfonyl chloride (25.5 mg, 17.3 μL, 222 μmol, equivalent: 2) were added. The reaction mixture was stirred at room temperature for 2 hours. An additional 10 uL of methanesulfonyl chloride was added and stirring was continued for 30 minutes. The reaction mixture was diluted with EtOAc and the organic layer was washed with 1M HCl (3 × 10 _{mL), saturated NaCl 3} (3 × 10 mL), and saturated NaCl (1 × 20 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo to give the crudely labeled compound, which was used in the next step without further purification, LC-MS: 528.3 [MH ⁺ ].

b) Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-{[(1R, R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) In a 20 mL sealed tube of pyridine-2-carbonyl] amino} butanoate, (rac) -trans-ethyl 2-ethyl-2- (5- (3-methoxyazetidine-1-yl) -6-((-2) -(((Methylsulfonyl) oxy) methyl) cyclopropyl) methoxy) picolinamide) butanoate (64 mg, 121 μmol, equivalent: 1) was combined with acetonitrile (10 mL) under an atmosphere of argon to obtain a colorless solution. .. TBAF in THF (606 μL, 606 μmol, equivalent: 5) was added and the reaction mixture was heated to 80 ° C. for 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl (3 x 25 mL) and brine (1 x 25 mL). The crude product was purified by column chromatography (SiO ₂ , 5 g, hept./ EtOAc) to give the title compound (19 mg, 35%) as a colorless oil, MS (ISP): 452.351 [ MH ⁺ ].

Example 4
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} butanoate and ethyl 2-ethyl-2-{[6-{[(1S, 2R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart

実施例１ａに記載した手順と同様にして、５−ブロモ−６−クロロピコリン酸（ＣＡＮ ９５９９５８−２５−９）を、（rac）−trans−（−２−（（tert−ブチルジメチルシリル）メトキシ）シクロプロピル）メタノール（ＣＡＮ １２４２００−３７−９）と反応させて、標記化合物を淡黄色の油状物として得た、ＭＳ（ＩＳＰ）：４１８．１６２ ［ＭＨ^＋］。 a) (Rac) -Cis-5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) picolinic acid

5-Bromo-6-chloropicolinic acid (CAN 959958-25-9) was added to (rac) -trans- (-2-((tert-butyldimethylsilyl) methoxy) in the same manner as in Example 1a. ) Cyclopropyl) methanol (CAN 124200-37-9) to give the title compound as a pale yellow oil, MS (ISP): 418.162 [MH ⁺ ].

実施例１ｂに記載した手順と同様にして、（rac）−Cis−５−ブロモ−６−（（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メトキシ）ピコリン酸を、エチル ２−アミノ−２−エチルブタノアート塩酸塩（ＣＡＮ １１３５２１９−２９−２）と反応させて、標記化合物を無色の油状物として得た、ＬＣ−ＭＳ（ＵＶピーク面積／ＥＳＩ）９０％、５５９．２０３２ ［ＭＨ^＋］。 b) (Rac) -Cis-ethyl 2- (5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) picoline amide) -2-ethylbutano art

Similar to the procedure described in Example 1b, (rac) -Cis-5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) picolinic acid. , Ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 90% 559.2032 [MH ⁺ ].

実施例１ｃに記載した手順と同様にして、（rac）−Cis−エチル ２−（５−ブロモ−６−（（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メトキシ）ピコリンアミド）−２−エチルブタノアートを、３−メトキシアゼチジン塩酸塩（ＣＡＮ １４８６４４−０９−１）と反応させて、標記化合物（６０mg、８５％）を淡黄色の油状物として得た、ＬＣ−ＭＳ（ＵＶピーク面積／ＥＳＩ）１００％、５６４．３４６９ ［ＭＨ^＋］。 c) (Rac) -Cis-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) ) Picoline amide) -2-ethylbutanoart

Similar to the procedure described in Example 1c, (rac) -Cis-ethyl 2-(5-bromo-6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) ) Picoline amide) -2-ethylbutanoate was reacted with 3-methoxyazetidine hydrochloride (CAN 148644-09-1) to give the title compound (60 mg, 85%) as a pale yellow oil. , LC-MS (UV peak area / ESI) 100%, 564.3469 [MH ⁺ ].

実施例１ｄに記載した手順と同様にして、（rac）−Cis−エチル ２−（６−（（−２−（（（tert−ブチルジメチルシリル）オキシ）メチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）−２−エチルブタノアートを、ＡｃＯＨで処理して、粗標記化合物を得、これを更に精製することなく次の反応工程で用いた、ＭＳ（ＩＳＰ）：５５０．３４３ ［ＭＨ^＋］。 d) (Rac) -Cis-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoart

Similar to the procedure described in Example 1d, (rac) -Cis-ethyl 2-(6-((-2-(((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methoxy) -5- (3-Methoxyazetidine-1-yl) picoline amide) -2-ethylbutanoate was treated with AcOH to give the crudely labeled compound, which was used in the next reaction step without further purification. MS (ISP): 550.343 [MH ⁺ ].

実施例３ａに記載した手順と同様にして、（rac）−Cis−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアートを、塩化メタンスルホニルと反応させて、粗標記化合物を得、これを更に精製することなく次の反応工程で用いた、ＭＳ（ＩＳＰ）：５２８．３００ ［ＭＨ^＋］。 e) (Rac) -Cis-ethyl 2-ethyl-2- (5- (3-methoxyazetidine-1-yl) -6-((-2-(((methylsulfonyl) oxy) methyl) cyclopropyl)) Methoxy) picoline amide) butanoart

Similar to the procedure described in Example 3a, (rac) -Cis-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazeti). Din-1-yl) picoline amide) butanoate was reacted with methanesulfonyl chloride to give the crudely labeled compound, which was used in the next reaction step without further purification, MS (ISP): 528.300 [. MH ⁺ ].

f) Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-{[(1S, 2R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) Pylin-2-carbonyl] amino} butanoate Similar to the procedure described in Example 3b, (rac) -Cis-ethyl 2-ethyl-2- (5- (3-methoxyazetidine-1-yl) -6. -((-2-(((Methylsulfonyl) oxy) methyl) cyclopropyl) methoxy) picolinamide) butanoate was reacted with TBAF to give the title compound as a colorless oil, MS (ISP): 452. .351 [MH ⁺ ].

実施例１ｅに記載した手順と同様にして、（rac）−Cis−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例４ｄ）を、フルオロ−ヨード−メタンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＩＳＰ）：４８２．３７０ ［ＭＨ^＋］。 Example 5
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-) 1-yl) pyridine-2-carbonyl] amino} butanoart

Similar to the procedure described in Example 1e, (rac) -Cis-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazeti). Din-1-yl) picoline amide) butanoate (Example 4d) was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 482.370 [MH ⁺ ]. ..

実施例１ｅに記載した手順と同様にして、（rac）−Cis−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例４ｄ）を、フルオロ−ヨード−エタンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＩＳＰ）：４９６．３２４ ［ＭＨ^＋］。 Example 6
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate

Similar to the procedure described in Example 1e, (rac) -Cis-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazeti). Din-1-yl) picoline amide) butanoate (Example 4d) was reacted with fluoro-iodo-ethane to give the title compound as a colorless oil, MS (ISP): 496.324 [MH ⁺ ]. ..

Example 7
Ethyl 2-{[6- (cyclopropylmethoxy) -4-fluoro-5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} -2-ethylbutanoate

５mLの丸底フラスコ中で、エチル ２−（６−（シクロプロピルメトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）−２−エチルブタノアート（ＣＡＮ １７７８６７８−１４−０、２８mg、６６．７μmol、当量：１）を、ＤＭＦ（１．５mL）と合わせて、淡黄色の溶液を得た。Ｎ−ブロモスクシンイミド（２３．８mg、１３３μmol、当量：２）を加え、反応物を室温で３０分間撹拌した。混合物をＥｔＯＡｃで希釈し、水／ブライン（１×１５mL）及びブライン（２×１５mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮した。粗生成物を、カラムクロマトグラフィー（ＳｉＯ_２、５ｇ、ｈｅｐｔ．／ＥｔＯＡｃ）により精製して、標記化合物（２１mg、６３％）を無色の油状物として得た、ＭＳ（ＩＳＰ）：４９８．２２９ ［ＭＨ^＋］。 a) Ethyl 2- (4-bromo-6- (cyclopropylmethoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) -2-ethylbutanoate

Ethyl 2- (6- (cyclopropylmethoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) -2-ethylbutanoate (CAN 1778678-14-0) in a 5 mL round-bottom flask , 28 mg, 66.7 μmol, equivalent: 1) was combined with DMF (1.5 mL) to give a pale yellow solution. N-Bromosuccinimide (23.8 mg, 133 μmol, eq: 2) was added and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc and washed with water / brine (1 x 15 mL) and brine (2 x 15 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , 5 g, hept./ EtOAc) to give the title compound (21 mg, 63%) as a colorless oil, MS (ISP): 498.229 [ MH ⁺ ].

b) Ethyl 2-{[6- (cyclopropylmethoxy) -4-fluoro-5- (3-methoxyazetidine-1-yl) pyridine-2-carbonyl] amino} -2-ethylbutanoate 5 mL circle In the bottom flask, ethyl 2- (4-bromo-6- (cyclopropylmethoxy) -5- (3-methoxyazetidine-1-yl) picolinamide) -2-ethylbutanoate (21 mg, 42.1 μmol) , Equivalent: 1) and CsF (128 mg, 843 μmol, equivalent: 20) were combined with DMSO (500 μL) to give a white suspension. The reaction mixture was heated to 120 ° C. for 7 days, diluted with EtOAc and washed with brine (3 x 15 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (0.7 mg, 4%) as a white solid, LC-MS (UV peak area / ESI) 100%, 438.2417 [MH ^+. ].

Example 8
Ethyl 2-ethyl-2-({6- [3- (fluoromethoxy) -2,2-dimethylpropoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate

実施例１ａに記載した手順と同様にして、５−ブロモ−６−クロロピコリン酸（ＣＡＮ ９５９９５８−２５−９）を、３−（ベンジルオキシ）−２，２−ジメチルプロパン−１−オール（ＣＡＮ ６６５８２−３２−９）と反応させて、標記化合物を白色の固体として得た、ＭＳ（ＩＳＰ）：３９４．０６０ ［ＭＨ^＋］。 a) 6- (3- (benzyloxy) -2,2-dimethylpropoxy) -5-bromopicolinic acid

5-Bromo-6-chloropicolinic acid (CAN 959958-25-9) was added to 3- (benzyloxy) -2,2-dimethylpropan-1-ol (CAN) in a similar manner to the procedure described in Example 1a. Reaction with 66582-32-9) gave the title compound as a white solid, MS (ISP): 394.060 [MH ⁺ ].

実施例１ｂに記載した手順と同様にして、６−（３−（ベンジルオキシ）−２，２−ジメチルプロポキシ）−５−ブロモピコリン酸を、エチル ２−アミノ−２−エチルブタノアート塩酸塩（ＣＡＮ １１３５２１９−２９−２）と反応させて、標記化合物を黄色の油状物として得た、ＭＳ（ＩＳＰ）：５３５．２００ ［ＭＨ^＋］。 b) Ethyl 2- (6- (3- (benzyloxy) -2,2-dimethylpropoxy) -5-bromopicoline amide) -2-ethylbutanoate

6- (3- (benzyloxy) -2,2-dimethylpropoxy) -5-bromopicolinic acid was added to ethyl 2-amino-2-ethylbutanoate hydrochloride in the same manner as in Example 1b. Reaction with (CAN 1135219-29-2) gave the title compound as a yellow oil, MS (ISP): 535.200 [MH ⁺ ].

実施例１ｃに記載した手順と同様にして、エチル ２−（６−（３−（ベンジルオキシ）−２，２−ジメチルプロポキシ）−５−ブロモピコリンアミド）−２−エチルブタノアートを、３−メトキシアゼチジン塩酸塩（ＣＡＮ １４８６４４−０９−１）と反応させて、標記化合物（６８０mg、８８％）を淡黄色の油状物として得た、ＭＳ（ＩＳＰ）：５４２．３５７ ［ＭＨ^＋］。 c) Ethyl 2- (6- (3- (benzyloxy) -2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) -2-ethylbutanoate

Ethyl 2- (6- (3- (benzyloxy) -2,2-dimethylpropoxy) -5-bromopicoline amide) -2-ethylbutanoate, 3 in the same procedure as described in Example 1c. -Methoxyasetidine hydrochloride (CAN 148644-09-1) was reacted to give the title compound (680 mg, 88%) as a pale yellow oil, MS (ISP): 542.357 [MH ⁺ ].

１００mLの丸底フラスコ中で、エチル ２−（６−（３−（ベンジルオキシ）−２，２−ジメチルプロポキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）−２−エチルブタノアート（６６５mg、１．２３mmol、当量：１）を、ＥｔＯＡｃ（３０mL）及びＭｅＯＨ（３mL）と合わせて、淡黄色の溶液を得た。Ｐｄ−Ｃ担持炭（６００mg、５．６４mmol、当量：４．５９）を加えた。混合物を水素雰囲気下で４８時間撹拌した。反応混合物をセライトに通して濾過し、有機溶媒を減圧下で除去して、目標化合物（５２３mg、９４％）を白色の固体として得た、ＭＳ（ＩＳＰ）：４５２．３５１ ［ＭＨ^＋］。 d) Ethyl 2-ethyl-2- (6- (3-hydroxy-2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoate

Ethyl 2-(6- (3- (benzyloxy) -2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) -2-ethyl in a 100 mL round bottom flask Butanoate (665 mg, 1.23 mmol, equivalent: 1) was combined with EtOAc (30 mL) and MeOH (3 mL) to give a pale yellow solution. Pd-C-supported charcoal (600 mg, 5.64 mmol, equivalent: 4.59) was added. The mixture was stirred under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered through Celite and the organic solvent was removed under reduced pressure to give the target compound (523 mg, 94%) as a white solid, MS (ISP): 452.351 [MH ⁺ ].

e) Ethyl 2-ethyl-2- ({6- [3- (fluoromethoxy) -2,2-dimethylpropoxy] -5- (3-methoxyazetidine-1-yl) pyridine-2-carbonyl} amino) Butanoart Ethyl 2-ethyl-2- (6- (3-hydroxy-2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) picolin, similar to the procedure described in Example 1e. Amide) Butanoate was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 484.237 [MH ⁺ ].

Example 9
(+)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart

（Rac）−trans−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例１ｄ）を、分取キラルＨＰＬＣ（Column Chiralpak AD、９０％ヘプタン／１０％エタノール及びＮＨ_４ＯＡｃ）に付した。有機溶媒を減圧下で除去し、残留物をＥｔＯＡｃで希釈した。有機相を水（３×５０mL）及びブライン（１×５０mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮して、標記化合物を淡黄色の油状物として得た、ＬＣ−ＭＳ（ＵＶピーク面積／ＥＳＩ）１００％、４５０．２６２４ ［ＭＨ^＋］。 a) (+)-trans-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoate

(Rac) -trans-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) Butanoate (implemented) Example 1d) was subjected to preparative chiral HPLC (Column Chiralpak AD, 90% heptan / 10% ethanol and NH _{4 OAc).} The organic solvent was removed under reduced pressure and the residue was diluted with EtOAc. The organic phase was washed with water (3 x 50 mL) and brine (1 x 50 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo to give the title compound as a pale yellow oil, LC-MS (UV peak area / ESI) 100%, 450.2624 [MH ⁺ ]. ..

b) (+)-trans-ethyl 2-ethyl-2-{[6-({-2- [(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) Pylin-2-carbonyl] amino} butanoate In a 5 mL round bottom flask, (+)-trans-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-Methoxyazetidine-1-yl) picolinamide) Butanoate (56 mg, 125 μmol, equivalent: 1) was combined with DMF (1 mL) to give a pale yellow solution. Sodium hydride (24.9 mg, 623 μmol, equivalent: 5) on the mineral oil was added and the reaction mixture was stirred at room temperature for 30 minutes. Fluoroiodo-methane (99.6 mg, 42 μL, 623 μmol, equivalent: 5) was added and stirring was continued for 90 minutes. The reaction mixture was diluted with EtOAc and washed with brine (3 x 10 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , 5 g, hept./ EtOAc) to give the title compound (10 mg, 17%) as a colorless oil, MS (ISP): 482.319 [. MH ⁺ ].

Example 10
(-)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(Fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart

実施例９ａに記載した手順と同様にして、（rac）−trans−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例１ｄ）を、分取キラルＨＰＬＣに付して、標記化合物を淡黄色の油状物として得た、ＬＣ−ＭＳ（ＵＶピーク面積／ＥＳＩ）９９％、４５０．２６３１ ［ＭＨ^＋］。 a) (-)-Trans-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoate Or mirror image isomer

Similar to the procedure described in Example 9a, (rac) -trans-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazeti). Gin-1-yl) picoline amide) butanoate (Example 1d) was subjected to preparative chiral HPLC to give the title compound as a pale yellow oil, LC-MS (UV peak area / ESI) 99%. , 4520631 [MH ⁺ ].

b) (-)-trans-ethyl 2-ethyl-2-{[6-({-2- [(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) Pylin-2-carbonyl] amino} butanoate Similar to the procedure described in Example 9b, (-)-trans-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy). ) -5- (3-Methoxyazetidine-1-yl) picolinamide) butanoate was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 482.319. [MH ⁺ ].

ａ） （−）−trans−２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタン酸

１０mLの丸底フラスコ中で、（−）−trans−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例１０ａ、１１７mg、２６０μmol、当量：１）を、ＴＨＦ（２mL）、ＭｅＯＨ（２．２mL）及び水（２mL）と合わせて、無色の溶液を得た。ＫＯＨ（７３mg、１．３mmol、当量：５）を加えた。混合物を９０℃で１８時間撹拌した。有機溶媒を減圧下で除去した。水相をｐＨ ２（１Ｍ ＨＣｌ）に調整し、ＥｔＯＡｃ（３×５mL）で抽出した。合わせた抽出物をブライン（１×１０mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、そして濾過した。溶媒を減圧下で除去して、粗標記化合物（１１０mg、定量）を無色の油状物として得、これを更に精製することなく次の反応工程で用いた、ＬＣ−ＭＳ（ＥＳ）：４２０．３ ［Ｍ−Ｈ⁻］。 Example 11
(-)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carbonyl] amino} butanoart

a) (-)-trans-2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoic acid

In a 10 mL round bottom flask, (-)-trans-ethyl 2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-) Il) picoline amide) butanoate (Example 10a, 117 mg, 260 μmol, equivalent: 1) was combined with THF (2 mL), MeOH (2.2 mL) and water (2 mL) to obtain a colorless solution. KOH (73 mg, 1.3 mmol, equivalent: 5) was added. The mixture was stirred at 90 ° C. for 18 hours. The organic solvent was removed under reduced pressure. The aqueous phase was adjusted to pH 2 (1M HCl) and extracted with EtOAc (3 x 5 mL). The combined extracts were washed with brine (1 x 10 mL), dried over Na ₂ SO ₄ , and filtered. The solvent was removed under reduced pressure to give the crudely labeled compound (110 mg, quantitative) as a colorless oil, which was used in the next reaction step without further purification, LC-MS (ES): 420.3. ^[M-H -].

b) (-)-trans-fluoromethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- In a 50 mL test tube of 2-carbonyl] amino} butanoate, K ₂ CO ₃ (32.5 mg, 235 μmol, equivalent: 3) was combined with DMF (2 mL) to give a white suspension. (-)-Trans-2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) Butanoic acid (33 mg) , 78.3 μmol, equivalent: 1) and fluoro-iodo-methane (37.6 mg, 15.9 μL, 235 μmol, equivalent: 3). Stirring was continued for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO ₂ , 5 g, hept./ EtOAc) to give the title compound (23 mg, 65%) as a colorless oil, MS (ISP): 454.308 [ MH ⁺ ].

Example 12
(+)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart

実施例１１ａに記載した手順と同様にして、（＋）−trans−エチル ２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノアート（実施例９ａ）を、ＫＯＨで処理して、標記化合物を白色の固体として得た、ＭＳ（ＩＳＰ）：４２２．２８１ ［ＭＨ^＋］。 a) (+)-trans-2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoic acid

Similar to the procedure described in Example 11a, (+)-trans-ethyl 2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazeti). Din-1-yl) picoline amide) butanoate (Example 9a) was treated with KOH to give the title compound as a white solid, MS (ISP): 422.281 [MH ⁺ ].

b) (+)-trans-fluoromethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart Similar to the procedure described in Example 11b, (+)-trans-2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5). -(3-Methoxyazetidine-1-yl) picolinamide) butanoic acid was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ISP): 454.308 [MH. ⁺ ].

実施例１１ｂに記載した手順と同様にして、（＋）−trans−２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタン酸（実施例１２ａ）を、フルオロ−ヨード−エタンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＩＳＰ）：４６８．３１３ ［ＭＨ^＋］。 Example 13
(+)-Trans-2-fluoroethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart

Similar to the procedure described in Example 11b, (+)-trans-2-ethyl-2-(6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine) -1-yl) picoline amide) butanoic acid (Example 12a) was reacted with fluoro-iodo-ethane to give the title compound as a colorless oil, MS (ISP): 468.313 [MH ⁺ ]. ..

実施例１１ｂに記載した手順と同様にして、（−）−trans−２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタン酸（実施例１１ａ）を、フルオロ−ヨード−エタンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＩＳＰ）：４６８．３１３ ［ＭＨ^＋］。 Example 14
(-)-Trans-2-fluoroethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart

Similar to the procedure described in Example 11b, (-)-trans-2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine). -1-yl) picoline amide) butanoic acid (Example 11a) was reacted with fluoro-iodo-ethane to give the title compound as a colorless oil, MS (ISP): 468.313 [MH ⁺ ]. ..

ａ） ビス（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル ブタンジオアート

２Ｌの１口丸底フラスコに、撹拌機、Dean-Starkトラップ及び冷却器を備えた。フラスコに、無水コハク酸（６４ｇ、０．６４mol、１当量）、ｌ−メントール（１９９．８８ｇ、１．３mol、２当量）、ｐ−トルエンスルホン酸一水和物（１．１ｇ、６．３９mmol、０．０１当量）及びトルエン（tolune）（５７６mL）を入れた。混合物を還流下で２４時間加熱し、２５℃に冷却し、ヘキサン（６４０mL）で希釈し、そして飽和重炭酸ナトリウム（８００mL）、メタノール（３２０mL）及び水（３２０mL）の混合物に注いだ。層を分離し、水相をヘキサン（２×３２０mL）で抽出した。有機相を合わせ、ブライン（６４０mL）で洗浄し、硫酸ナトリウムで乾燥し、そして濾過した。溶媒を減圧下で除去し、粗生成物をメタノール（２４０mL）に溶解した。溶液を＋４℃に１６時間冷却して、無色の結晶を形成し、これを吸引濾過により収集した。結晶を、メタノール（２４０mL）からの再結晶化により精製して、純粋なビス（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル ブタンジオアート（２１２ｇ、８４％）を得た。
ＳＯＲ値：≒２５℃で［−８７．６４°］、ＣＨＣｌ_３中１．０１３２％溶液。 Example 15
3-Fluoropropyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart

a) Bis (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl butanegioart

A 2 L single-necked round-bottom flask was equipped with a stirrer, a Dean-Stark trap and a cooler. Succinic anhydride (64 g, 0.64 mol, 1 eq), l-menthol (199.88 g, 1.3 mol, 2 eq), p-toluenesulfonic acid monohydrate (1.1 g, 6.39 mmol) in a flask. , 0.01 eq) and toluene (576 mL). The mixture was heated under reflux for 24 hours, cooled to 25 ° C., diluted with hexane (640 mL) and poured into a mixture of saturated sodium bicarbonate (800 mL), methanol (320 mL) and water (320 mL). The layers were separated and the aqueous phase was extracted with hexane (2 x 320 mL). The organic phases were combined, washed with brine (640 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the crude product was dissolved in methanol (240 mL). The solution was cooled to + 4 ° C. for 16 hours to form colorless crystals, which were collected by suction filtration. Crystals are purified by recrystallization from methanol (240 mL) to pure bis (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl butanegioart (212 g, 84%). ) Was obtained.
SOR value: [-87.64 °] at about 25 ° C., 1.0132% solution in _{CHCl 3.}

ＴＨＦ中ブチルリチウム（１５２．２mmol、８４mL）の１．８Ｍ溶液を、Ｎ_２雰囲気下、０℃でＴＨＦ（２２５mL）に加えた。撹拌しながら、リチウムテトラメチルピペリジド（２８．２mL、１６７mmol）を２０分間かけて滴下した。撹拌を０℃で１時間続けた。次に、反応混合物を−７８℃に冷却した。ＴＨＦ（６０mL）中のビス（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル ブタンジオアート（３０ｇ、７６．１mmol）の溶液を、２０分間かけて滴下した。黄色の溶液を１時間撹拌した。ブロモクロロメタン（４．０８mL、６０．９１mmol）を２０分間かけて滴下した。混合物を−７８℃で３時間撹拌した。飽和ＮＨ_４Ｃｌ水溶液（１２０mL）を加えた。２５℃で３０分間撹拌した後、混合物をＥｔＯＡｃ（３×１５０mL）で抽出した。合わせた有機層をブライン（２００mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、そして真空中で濃縮した。粗生成物を、カラムクロマトグラフィー（ＳｉＯ_２、１００〜２００メッシュ、０．５〜１％の酢酸エチル及びヘキサン）により精製して、標記化合物（３８ｇ、４２％）を無色の結晶として得た。メタノール（３８０mL）からこの物質の再結晶化が、純粋な１，２−ビス（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル（１Ｓ，２Ｓ）−シクロプロパン−１，２−ジカルボキシラート（２７ｇ、３６％）を得た。
ＳＯＲ値：≒２５℃で［＋１８．１８°］、ＣＨＣｌ_３中１．０２８８％溶液。 b) 1,2-Bis (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S) -cyclopropane-1,2-dicarboxylate

In THF butyllithium (152.2mmol, 84mL) and 1.8M solution of, _{N 2} atmosphere, was added to THF (225 mL) at 0 ° C.. Lithium tetramethylpiperidide (28.2 mL, 167 mmol) was added dropwise over 20 minutes with stirring. Stirring was continued at 0 ° C. for 1 hour. The reaction mixture was then cooled to −78 ° C. A solution of bis (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl butanedioart (30 g, 76.1 mmol) in THF (60 mL) was added dropwise over 20 minutes. The yellow solution was stirred for 1 hour. Bromochloromethane (4.08 mL, 60.91 mmol) was added dropwise over 20 minutes. The mixture was stirred at −78 ° C. for 3 hours. Addition of saturated aqueous _NH 4 Cl (120 mL). After stirring at 25 ° C. for 30 minutes, the mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , 100-200 mesh, 0.5-1% ethyl acetate and hexane) to give the title compound (38 g, 42%) as colorless crystals. Recrystallization of this material from methanol (380 mL) is pure 1,2-bis (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S) -cyclopropane. -1,2-dicarboxylate (27 g, 36%) was obtained.
SOR value: [+ 18.18 °] at ≈25 ° C, 1.0288% solution in _{CHCl 3.}

イソプロパノール（２５０mL）中の１，２−ビス（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル（１Ｓ，２Ｓ）−シクロプロパン−１，２−ジカルボキシラート（２５ｇ、６１．５８mmol）の溶液に、５Ｍ ＮａＯＨ溶液（１３．５４mL、６７．７３mmol）を２５℃で加えた。混合物を７０℃で１６時間撹拌した。有機溶媒を減圧下で除去した。水（２００mL）を加え、混合物をジエチルエーテル（２×１５０mL）で洗浄した。水層を２Ｎ ＨＣｌ（ｐＨ約２）で酸性化し、酢酸エチル （３×２５０mL）で抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥し、濾過し、減圧下で濃縮して、（１Ｓ，２Ｓ）−２−（｛［（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル］オキシ｝カルボニル）シクロプロパン−１−カルボン酸（１１．４ｇ、６９％）をオフホワイトの半固体として得た。 c) (1S, 2S) -cyclopropane-1,2-dicarboxylic acid mono-((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl) ester

1,2-Bis (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S) -cyclopropane-1,2-dicarboxylate (1R, 2S, 5R) in isopropanol (250 mL) A 5M NaOH solution (13.54 mL, 67.73 mmol) was added to the 25 g, 61.58 mmol) solution at 25 ° C. The mixture was stirred at 70 ° C. for 16 hours. The organic solvent was removed under reduced pressure. Water (200 mL) was added and the mixture was washed with diethyl ether (2 x 150 mL). The aqueous layer was acidified with 2N HCl (pH about 2) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were _{dried over Na 2} SO ₄ , filtered, concentrated under reduced pressure and (1S, 2S) -2-({[(1R, 2S, 5R) -5-methyl-2- (propane). -2-yl) cyclohexyl] oxy} carbonyl) cyclopropane-1-carboxylic acid (11.4 g, 69%) was obtained as an off-white semi-solid.

ＴＨＦ（２００mL）中の（１Ｓ，２Ｓ）−シクロプロパン−１，２−ジカルボン酸 モノ−（（１Ｒ，２Ｓ，５Ｒ）−２−イソプロピル−５−メチル−シクロヘキシル）エステル（２０ｇ、７４．６３mmol）の撹拌した溶液に、ＴＨＦ中のボランの１Ｍ溶液（５６mL）を−７８℃で滴下した。混合物を２５℃で１時間撹拌し、ＮＨ_４Ｃｌ水溶液（１５０mL）でクエンチした。有機溶媒を減圧下で除去した。水を加え（５０mL）、混合物を酢酸エチル （２×１００mL）で抽出した。合わせた有機層をブライン（８０mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、そして減圧下で濃縮した。粗生成物を、シリカゲルカラムクロマトグラフィー（１５〜１９％酢酸エチル／ヘキサン）により精製して、（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロパン−１−カルボキシラート（１３．６６ｇ、７２％）を帯黄色の半固体として得た。 d) (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S) -2- (hydroxymethyl) cyclopropane-1-carboxylate

(1S, 2S) -cyclopropane-1,2-dicarboxylic acid mono-((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl) ester in THF (200 mL) (20 g, 74.63 mmol) A 1M solution (56 mL) of borane in THF was added dropwise at −78 ° C. to the stirred solution of. The mixture was stirred for 1 hour at 25 ° C., and quenched with aqueous _NH 4 Cl (150 mL). The organic solvent was removed under reduced pressure. Water was added (50 mL) and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (15-19% ethyl acetate / hexane) and (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S). ) -2- (Hydroxymethyl) cyclopropane-1-carboxylate (13.66 g, 72%) was obtained as a yellowish semi-solid.

ＤＭＦ（１４０mL）中の（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロパン−１−カルボキシラート（２０ｇ、７８．７４mmol）の撹拌した溶液に、ＮａＨ（４．７２ｇ、１１８．１１mmol）を０℃で加えた。混合物を２５℃で３０分間撹拌した。臭化ベンジル（１８．７０mL、１５７．４８mmol）を加え、撹拌を２５℃で３０分間続けた。ＮＨ_４Ｃｌ水溶液（１５０mL）を加え、混合物をＥｔＯＡｃ（２×１５０mL）で抽出した。合わせた有機層を水（３×１２０mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、そして減圧下で濃縮した。粗生成物を、シリカゲルカラムクロマトグラフィー（１．９％ ＥｔＯＡｃ／ヘキサン）により精製して、（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロパン−１−カルボキシラート（２２ｇ、８１％）を淡黄色の油状物として得た。 e) (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S) -2-[(benzyloxy) methyl] cyclopropane-1-carboxylate

(1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S) -2- (hydroxymethyl) cyclopropane-1-carboxylate (20 g,) in DMF (140 mL) NaH (4.72 g, 118.11 mmol) was added to the stirred solution of 78.74 mmol) at 0 ° C. The mixture was stirred at 25 ° C. for 30 minutes. Benzyl bromide (18.70 mL, 157.48 mmol) was added and stirring was continued at 25 ° C. for 30 minutes. Aqueous NH ₄ Cl (150 mL) was added and the mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with water (3 x 120 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1.9% EtOAc / Hexanes) and (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S). -2-[(benzyloxy) methyl] cyclopropane-1-carboxylate (22 g, 81%) was obtained as a pale yellow oil.

ＴＨＦ（２００mL）中の（１Ｒ，２Ｓ，５Ｒ）−５−メチル−２−（プロパン−２−イル）シクロヘキシル（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロパン−１−カルボキシラート（１０ｇ、２９．０７mmol）の撹拌した溶液に、ＬＡＨ（５８．１４mL、ＴＨＦ中１Ｍ）を０℃で加えた。反応混合物を０℃で４０分間撹拌し、ＮＨ_４Ｃｌ水溶液（１００mL）でクエンチした。有機溶媒を減圧下で除去した。溶液を酢酸エチル （３×１００mL）で抽出した。合わせた有機層を乾燥し、粗生成物をシリカゲルカラムクロマトグラフィー（３０〜３５％酢酸エチル／ヘキサン）を用いて精製して、［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メタノール（５．３３ｇ、９５％）を淡黄色の油状物として得た。 f) [(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methanol

(1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl (1S, 2S) -2-[(benzyloxy) methyl] cyclopropane-1-carboxylate in THF (200 mL) LAH (58.14 mL, 1 M in THF) was added to the stirred solution (10 g, 29.07 mmol) at 0 ° C. The reaction mixture was stirred for 40 min at 0 ° C., and quenched with aqueous _NH 4 Cl (100 mL). The organic solvent was removed under reduced pressure. The solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers are dried and the crude product is purified using silica gel column chromatography (30-35% ethyl acetate / hexane) with [(1S, 2S) -2-[(benzyloxy) methyl] cyclo. Propyl] methanol (5.33 g, 95%) was obtained as a pale yellow oil.

ＤＭＦ（４５mL）中の５−ブロモ−６−クロロピリジン−２−カルボン酸（ＣＡＮ ９５９９５８−２５−９、４ｇ、１９．８０mmol）の溶液に、ＮａＨ（２．７７ｇ、６９．３１mmol）を０℃で少量ずつ加え、０℃で２０分間撹拌した。ＤＭＦ（１５mL）中の［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メタノール（４．１８ｇ、２１．７８mmol）を０℃で少量ずつ加えた。混合物を２５℃で１５分間撹拌し、８０℃に３時間加熱し、２５℃に冷却し、そして２Ｎ ＨＣｌ水溶液でｐＨを約２にクエンチした。水（１００mL）を加え、混合物をＥｔＯＡｃ（３×１５０mL）で抽出した。合わせた有機層を水（４×５０mL）及びブライン（５０mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、減圧下で濃縮して、６−｛［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−ブロモピリジン−２−カルボン酸（７．７ｇ、９９％）をオフホワイトの粘着性液体として得た。 g) 6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-carboxylic acid

NaH (2.77 g, 69.31 mmol) in a solution of 5-bromo-6-chloropyridin-2-carboxylic acid (CAN 959958-25-9, 4 g, 19.80 mmol) in DMF (45 mL) at 0 ° C. Was added little by little, and the mixture was stirred at 0 ° C. for 20 minutes. [(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methanol (4.18 g, 21.78 mmol) in DMF (15 mL) was added in small portions at 0 ° C. The mixture was stirred at 25 ° C. for 15 minutes, heated to 80 ° C. for 3 hours, cooled to 25 ° C. and quenched to pH about 2 with 2N HCl aqueous solution. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (4 x 50 mL) and brine (50 mL), dried with Na ₂ SO ₄ , concentrated under reduced pressure and 6-{[(1S, 2S) -2-[(benzyl). Oxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-carboxylic acid (7.7 g, 99%) was obtained as an off-white sticky liquid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 76.78%, holding time = 2.60 minutes, MS calculated value: 391, MS measured value: 391.8 [M + H].

ＤＭＦ（１００mL）中の６−｛［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−ブロモピリジン−２−カルボン酸（１５．５ｇ、３９．５４mmol）の溶液に、ＤＩＰＥＡ（２７．４９mL、１５８．１６mmol）、エチル ２−アミノ−２−エチルブタノアート（ＣＡＮ １８９６３１−９６−７、７．７３ｇ、３９．５４mmol）及びＴＢＴＵ（１５．２５ｇ、４７．４４９mmol）を加えた。反応混合物を２５℃で１６時間撹拌し、水（１７０mL）に注ぎ、そしてＥｔＯＡｃ（３×２００mL）で抽出した。合わせた有機層を水（４×１２０mL）及びブライン（１００mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、そして乾燥させた。粗生成物を、シリカゲルカラムクロマトグラフィー（２５％酢酸エチル／ヘキサン）を介して精製して、エチル ２−［（６−｛［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−ブロモピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（２０．５ｇ、９７％）を淡褐色の油状物として得た。 h) Ethyl 2-[(6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-yl) formamide] -2-ethylbutanoart

Of 6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-carboxylic acid (15.5 g, 39.54 mmol) in DMF (100 mL) In solution, DIPEA (27.49 mL, 158.16 mmol), ethyl 2-amino-2-ethylbutanoate (CAN 189631-96-7, 7.73 g, 39.54 mmol) and TBTU (15.25 g, 47. 449 mmol) was added. The reaction mixture was stirred at 25 ° C. for 16 hours, poured into water (170 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (4 x 120 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and dried. The crude product was purified via silica gel column chromatography (25% ethyl acetate / hexane) and ethyl 2-[(6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl. ] Methoxy} -5-bromopyridin-2-yl) formamide] -2-ethylbutanoate (20.5 g, 97%) was obtained as a light brown oil.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 91.47%, holding time = 2.58 minutes, MS calculated value: 533, MS measured value: 533.0 [M + H].

トルエン（１６０mL）中のエチル ２−［（６−｛［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−ブロモピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（４ｇ、７．５０mmol）の溶液に、３−メトキシアゼチジン（１．３９ｇ、１１．２６mmol）及び炭酸セシウム（７．３３ｇ、２２．５１mmol）を加えた。混合物をアルゴンで１０分間脱気した。Rac−ＢＩＮＡＰ（０．９３５ｇ、１．５０mmol）及びＰｄ（II）アセタート（０．３４ｇ、１．５０mmol）を加えた。混合物を１１０℃に３時間加熱し、ＥｔＯＡｃ（１００mL）で希釈し、セライトベッドで濾過し、そしてＥｔＯＡｃ（３×１００mL）で洗浄した。濾液を濃縮し、粗生成物をシリカゲルカラムクロマトグラフィー（４２〜５０％酢酸エチル／ヘキサン）で精製して、エチル ２−［（６−｛［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（３．１ｇ、７６％）を淡褐色の油状物として得た。 i) Ethyl 2-[(6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-yl) ) Formamide] -2-ethylbutanoart

Ethyl 2-[(6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-yl) formamide] -2- in toluene (160 mL) To a solution of ethyl butanoate (4 g, 7.50 mmol) was added 3-methoxyazetidine (1.39 g, 11.26 mmol) and cesium carbonate (7.33 g, 22.51 mmol). The mixture was degassed with argon for 10 minutes. Rac-BINAP (0.935 g, 1.50 mmol) and Pd (II) acetate (0.34 g, 1.50 mmol) were added. The mixture was heated to 110 ° C. for 3 hours, diluted with EtOAc (100 mL), filtered through a Celite bed and washed with EtOAc (3 x 100 mL). The filtrate is concentrated and the crude product is purified by silica gel column chromatography (42-50% ethyl acetate / hexane) with ethyl 2-[(6-{[(1S, 2S) -2-[(benzyloxy)). Methyl] cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2-yl) formamide] -2-ethylbutanoate (3.1 g, 76%) in a light brown oil Obtained as.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity was 96.74%, holding time = 2.37 minutes, MS calculated value: 539, MS measured value: 539.9 [M + H ⁺ ].

ＥｔＯＡｃ：ＭｅＯＨ（１０：１）（７３５mL）中のエチル ２−［（６−｛［（１Ｓ，２Ｓ）−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（２６ｇ、４８．２４mmol）の撹拌した溶液を、３０分間脱気した。Ｐｄ／Ｃ（１０％）（６．５ｇ）を加えた。混合物を４０PSIで水素雰囲気下、２５℃で２８時間水素化し、セライトベッドで濾過し、そして１０％ ＭｅＯＨ／ＥｔＯＡｃ（４×２００mL）で洗浄した。濾液を減圧下で蒸発させて、粗生成物を得た。粗生成物を、シリカゲルカラムクロマトグラフィー（１０〜５０％ ＥｔＯＡｃ：ヘキサン）を適用して精製して、エチル ２−エチル−２−［（６−｛［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］ブタノアート（１９．３ｇ、８９％）を無色の粘着性液体として得た。
ＳＯＲ値：≒２０℃で［＋１５．５１°］、ＭｅＯＨ中０．２５１４％。 j) Ethyl 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Il) formamide] butanoat

EtOAc: Ethyl 2-[(6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-methoxyazeti) in MeOH (10: 1) (735 mL) A stirred solution of gin-1-yl) pyridin-2-yl) formamide] -2-ethylbutanoate (26 g, 48.24 mmol) was degassed for 30 minutes. Pd / C (10%) (6.5 g) was added. The mixture was hydrogenated at 40 PSI under a hydrogen atmosphere at 25 ° C. for 28 hours, filtered through a Celite bed and washed with 10% MeOH / EtOAc (4 x 200 mL). The filtrate was evaporated under reduced pressure to give a crude product. The crude product was purified by applying silica gel column chromatography (10-50% EtOAc: Hexanes) to ethyl 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl). ) Cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-yl) formamide] butanoate (19.3 g, 89%) was obtained as a colorless sticky liquid.
SOR value: [+ 15.51 °] at ≈20 ° C, 0.2514% in MeOH.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity was 98.93%, holding time = 3.26 minutes, MS calculated value: 449, MS measured value: 449.9 [M + H ⁺ ].

２５mlの丸底フラスコ中で、エチル ２−エチル−２−［（６−｛［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］ブタノアート（１００mg、０．２２mmol）を、ＴＨＦ（２．０mL）、ＭｅＯＨ（２．２mL）及び水（２．０mL）と合わせて、淡黄色の溶液を得た。ＫＯＨペレット（６２mg、１．１１mmol）を加えた。混合物を９０℃に加熱した。１８時間後、有機溶媒を減圧下で除去した。水相を水（２０mL）で希釈し、ジエチルエーテル（２×１０mL）で抽出した。合わせた有機層を廃棄した。水相をｐＨ約２（１Ｍ ＨＣｌ）に調整し、ＥｔＯＡｃ（３×１５mL）で抽出した。合わせた有機層をブライン（１０mL）で洗浄し、乾燥し、濾過し、減圧下で乾燥させて、純粋な２−エチル−２−［（６−｛［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］ブタン酸（９０mg、９６％）を無色の粘着性の塊として得た。 k) 2-Ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-yl) ) Formamide] Butanoic acid

In a 25 ml round bottom flask, ethyl 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-) Il) Pyridine-2-yl) formamide] Butanoate (100 mg, 0.22 mmol) was combined with THF (2.0 mL), MeOH (2.2 mL) and water (2.0 mL) to obtain a pale yellow solution. rice field. KOH pellets (62 mg, 1.11 mmol) were added. The mixture was heated to 90 ° C. After 18 hours, the organic solvent was removed under reduced pressure. The aqueous phase was diluted with water (20 mL) and extracted with diethyl ether (2 x 10 mL). The combined organic layer was discarded. The aqueous phase was adjusted to pH about 2 (1M HCl) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and dried under reduced pressure to pure 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxy). Methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-yl) formamide] butanoic acid (90 mg, 96%) was obtained as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 95.49%, holding time = 2.00 minutes, MS calculated value: 419, MS measured value: 420.4 [M + H ⁺ ].

ＤＭＦ（５mL）中の２−エチル−２−［（６−｛［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］ブタン酸（２６０mg、０．６２mmol）の溶液に、Ｋ_２ＣＯ_３（２５６mg、１．８５mmol）及び３−｛［（４−メチルベンゼン）スルホニル］オキシ｝プロピル ４−メチルベンゼン−１−スルホナート（７１１mg、１．８５mmol）を加えた。反応混合物を２５℃で１６時間撹拌し、水に注ぎ、１（Ｎ）ＨＣｌ水溶液でクエンチし、そしてＥｔＯＡｃ（３×４０mL）で抽出した。合わせた有機層をブライン（３０mL）で洗浄し、乾燥し、濾過し、真空中で濃縮して、粗生成物を得、これをシリカカラム及びヘキサン中２０〜８０％ ＥｔＯＡｃを用いるcombiflashにより精製して、純粋な３−｛［（４−メチルベンゼン）スルホニル］オキシ｝プロピル ２−エチル−２−［（６−｛［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］ブタノアート（２５５mg、６５％）を無色の粘着性の塊として得た。 l) 3-{[(4-Methylbenzene) sulfonyl] oxy} propyl 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) pyridin-2-yl) formamide] Butanoart

2-Ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine) in DMF (5 mL) -2-yl) Formamide] In a solution of butanoic acid (260 mg, 0.62 mmol), K ₂ CO ₃ (256 mg, 1.85 mmol) and 3-{[(4-methylbenzene) sulfonyl] oxy} propyl 4-methyl Benzin-1-sulfonate (711 mg, 1.85 mmol) was added. The reaction mixture was stirred at 25 ° C. for 16 hours, poured into water, quenched with 1 (N) aqueous HCl and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (30 mL), dried, filtered and concentrated in vacuo to give the crude product, which was purified by a silica column and combiflash with 20-80% EtOAc in hexanes. And pure 3-{[(4-methylbenzene) sulfonyl] oxy} propyl 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5 -(3-Methoxyazetidine-1-yl) pyridin-2-yl) formamide] butanoate (255 mg, 65%) was obtained as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 90.68%, holding time = 3.48 minutes, MS calculated value: 633, MS measured value: 634.4 [M + H ⁺ ].

m) 3-Fluoropropyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] Amino} Butanoart 2-Ethyl-2- (6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5, similar to the procedure described in Example 11b. -(3-Methoxyazetidine-1-yl) picolinamide) butanoic acid (Example 12a) was reacted with fluoro-iodo-propane to give the title compound as a colorless oil, MS (ISP): 482.370 [MH ⁺ ].

実施例１１ｂに記載した手順と同様にして、（−）−trans−２−エチル−２−（６−（（−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタン酸（実施例１１ａ）を、フルオロ−ヨード−プロパンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＩＳＰ）：４８２．３１９ ［ＭＨ^＋］。 Example 16
3-Fluoropropyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart

Similar to the procedure described in Example 11b, (-)-trans-2-ethyl-2- (6-((-2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine). -1-yl) picoline amide) butanoic acid (Example 11a) was reacted with fluoro-iodo-propane to give the title compound as a colorless oil, MS (ISP): 482.319 [MH ⁺ ]. ..

Example 17
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) Methoxy] Pyridine-2-carboxamide

実施例１ａに記載した手順と同様にして、５−ブロモ−６−クロロピコリン酸（ＣＡＮ ９５９９５８−２５−９）を、３−オキセタンメタノール（ＣＡＮ ６２４６−０６−６）と反応させて、標記化合物を淡褐色の固体として得た、ＭＳ（ＩＳＰ）：２８７．９９８ ［ＭＨ^＋］。 a) 5-Bromo-6- (oxetane-3-ylmethoxy) picolinic acid

In the same procedure as described in Example 1a, 5-bromo-6-chloropicolinic acid (CAN 959958-25-9) was reacted with 3-oxetane methanol (CAN 6246-06-6) to carry out the title compound. Was obtained as a light brown solid, MS (ISP): 287.998 [MH ⁺ ].

実施例１１ｂに記載した手順と同様にして、５−ブロモ−６−（オキセタン−３−イルメトキシ）ピコリン酸を、ヨードメタンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＩＳＰ）：３０２．００３ ［ＭＨ^＋］。 b) Methyl 5-bromo-6- (oxetane-3-ylmethoxy) picolinate

Similar to the procedure described in Example 11b, 5-bromo-6- (oxetane-3-ylmethoxy) picolinic acid was reacted with iodomethane to give the title compound as a colorless oil, MS (ISP). : 302.003 [MH ⁺ ].

実施例１ｃに記載した手順と同様にして、メチル ５−ブロモ−６−（オキセタン−３−イルメトキシ）ピコリナートを、３−メトキシアゼチジン塩酸塩（ＣＡＮ １４８６４４−０９−１）と反応させて、標記化合物を淡黄色の油状物として得た、ＭＳ（ＩＳＰ）：３０９．２０９ ［ＭＨ^＋］。 c) Methyl 5- (3-methoxyazetidine-1-yl) -6- (oxetane-3-ylmethoxy) picolinate

Methyl 5-bromo-6- (oxetane-3-ylmethoxy) picolinate was reacted with 3-methoxyazetidine hydrochloride (CAN 148644-09-1) in a manner similar to that described in Example 1c and labeled. The compound was obtained as a pale yellow oil, MS (ISP): 309.209 [MH ⁺ ].

実施例１１ａに記載した手順と同様にして、メチル ５−（３−メトキシアゼチジン−１−イル）−６−（オキセタン−３−イルメトキシ）ピコリナートを、ＫＯＨで処理して、粗標記化合物を得、これを更に精製することなく次の反応工程で用いた。 d) 5- (3-Methoxyazetidine-1-yl) -6- (oxetane-3-ylmethoxy) picolinic acid

Methyl 5- (3-methoxyazetidine-1-yl) -6- (oxetane-3-ylmethoxy) picolinate was treated with KOH in the same procedure as described in Example 11a to obtain the crudely labeled compound. , This was used in the next reaction step without further purification.

５mLの丸底フラスコ中で、５−（３−メトキシアゼチジン−１−イル）−６−（オキセタン−３−イルメトキシ）ピコリン酸（４５mg、１５３μmol、当量：１）を、ＤＭＦ（１mL）と合わせて、淡黄色の溶液を得た。ＴＢＴＵ（５８．９mg、１８３μmol、当量：１．２）及びＤＩＰＥＡ（９８．８mg、１３４μL、７６５μmol、当量：５）を加えた。L-Leucinol（ＣＡＮ ７５３３−４０−６、５３．８mg、５８．６μL、４５９μmol、当量：３）を加え、混合物を室温で３０分間撹拌した。溶媒を減圧下で除去し、粗生成物をカラムクロマトグラフィー（ＳｉＯ_２、１０ｇ、ｈｅｐｔ．／ＥｔＯＡｃ）により精製して、標記化合物（４４mg、７３％）を無色の固体として得た、ＭＳ（ＩＳＰ）：３９４．３２６ ［ＭＨ^＋］。 e) (S) -N- (1-Hydroxy-4-methylpentane-2-yl) -5- (3-methoxyazetidine-1-yl) -6- (oxetane-3-ylmethoxy) picoline amide

In a 5 mL round bottom flask, combine 5- (3-methoxyazetidine-1-yl) -6- (oxetane-3-ylmethoxy) picolinic acid (45 mg, 153 μmol, equivalent: 1) with DMF (1 mL). To obtain a pale yellow solution. TBTU (58.9 mg, 183 μmol, equivalent: 1.2) and DIPEA (98.8 mg, 134 μL, 765 μmol, equivalent: 5) were added. L-Leucinol (CAN 7533-40-6, 53.8 mg, 58.6 μL, 459 μmol, equivalent: 3) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO ₂ , 10 g, hept./ EtOAc) to give the title compound (44 mg, 73%) as a colorless solid, MS (ISP). ): 394.326 [MH ⁺ ].

f) N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) Methoxy] Pyridine-2-carboxamide In a 10 mL round bottom flask, (S) -N- (1-hydroxy-4-methylpentane-2-yl) -5- (3-methoxyazetidine-1-yl) ) -6- (Oxetane-3-ylmethoxy) picolineamide (45 mg, 114 μmol, equivalent: 1) was combined with DMF (1 mL) to give a yellow solution, which was cooled to 0 ° C. Sodium hydride and a dispersion on mineral oil (13.7 mg, 343 μmol, equivalent: 3) were added and the mixture was allowed to warm to room temperature. After 15 minutes, 1-fluoro-2-iodoethane (99.5 mg, 47.4 μL, 572 μmol, equivalent: 5) was added and stirring was continued at room temperature. Addition of sodium hydride (equivalent: 3) and 1-fluoro-2-iodoethane (equivalent: 5) was repeated after 15, 17 and 20 hours. After stirring at room temperature for an additional 2 hours, the reaction mixture was diluted with EtOAc and washed with brine (3 x 10 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (6 mg, 12%) as a colorless oil, LC-MS (UV peak area / ESI) 99%, 440.2561 [MH ⁺ ]. ..

Example 18
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-[(oxetane-3-yl) methoxy] -5- (pyrrolidin-1-yl) pyridine- 2-Carboxamide

実施例１ｃに記載した手順と同様にして、メチル ５−ブロモ−６−（オキセタン−３−イルメトキシ）ピコリナート（実施例１７ｂ）を、ピロリジン（ＣＡＮ １２３−７５−１）と反応させて、標記化合物を淡黄色の油状物として得た、ＭＳ（ＩＳＰ）：２９３．１６２ ［ＭＨ^＋］。 a) Methyl 6- (oxetane-3-ylmethoxy) -5- (pyrrolidin-1-yl) picolinate

Methyl 5-bromo-6- (oxetane-3-ylmethoxy) picolinate (Example 17b) was reacted with pyrrolidine (CAN 123-75-1) in the same manner as in Example 1c to give the title compound. Was obtained as a pale yellow oil, MS (ISP): 293.162 [MH ⁺ ].

実施例１１ａに記載した手順と同様にして、メチル ６−（オキセタン−３−イルメトキシ）−５−（ピロリジン−１−イル）ピコリナートを、ＫＯＨで処理して、粗標記化合物を得、これを更に精製することなく次の反応工程で用いた、ＬＣ−ＭＳ（ＥＳ）：２７９．２ ［ＭＨ^＋］。 b) 5- (3-Methoxyazetidine-1-yl) -6- (oxetane-3-ylmethoxy) picolinic acid

Methyl 6- (oxetane-3-ylmethoxy) -5- (pyrrolidin-1-yl) picolinate was treated with KOH in the same manner as in Example 11a to give the crude compound, which was further added. LC-MS (ES): 279.2 [MH ⁺ ] used in the next reaction step without purification.

実施例１７ｅに記載した手順と同様にして、５−（３−メトキシアゼチジン−１−イル）−６−（オキセタン−３−イルメトキシ）ピコリン酸を、L-leucinolと反応させて、標記化合物を淡黄色の油状物として得た、ＭＳ（ＩＳＰ）：３７８．３２７ ［ＭＨ^＋］。 c) (S) -N- (1-hydroxy-4-methylpentane-2-yl) -6- (oxetane-3-ylmethoxy) -5- (pyrrolidin-1-yl) picoline amide

Similar to the procedure described in Example 17e, 5- (3-methoxyazetidine-1-yl) -6- (oxetane-3-ylmethoxy) picolinic acid was reacted with L-leucinol to obtain the title compound. Obtained as a pale yellow oil, MS (ISP): 378.327 [MH ⁺ ].

d) N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-[(oxetane-3-yl) methoxy] -5- (pyrrolidin-1-yl) Pyridine-2-carboxamide Similar to the procedure described in Example 17f, (S) -N- (1-hydroxy-4-methylpentane-2-yl) -6- (oxetane-3-ylmethoxy) -5- Picoline amide (pyrrolidine-1-yl) was reacted with 1-fluoro-2-iodoetane to give the title compound as a colorless oil, MS (ISP): 424.387 [MH ⁺ ].

Example 19
(1,1,2,2,3,3-hexajuuterio-3-fluoro-propyl) 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl]] Methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate

ＤＣＭ（１mL）中の１，１，２，２，３，３−ヘキサジュウテリオプロパン−１，３−ジオール（４６mg、０．５５mmol）の溶液に、２，６−ルチジン（０．２mL、１．６４mmol）及び塩化トシル（１５６mg、０．８２mmol、１．５当量）を加えた。反応混合物を２５℃で１７時間撹拌し、ＤＣＭ（１５mL）で希釈し、１Ｎ ＨＣｌ水溶液（１０mL）及び水（１０mL）で洗浄し、乾燥し、濾過し、そして真空中で濃縮した。粗生成物を、シリカゲルカラムクロマトグラフィー（ヘキサン中５〜３０％ ＥｔＯＡｃ）により精製して、標記化合物（５０mg、４１％）を無色の液体として得た。 a) (1,1,2,2,3,3-hexajuuterio-3-hydroxy-propyl) 4-methylbenzenesulfonate

2,6-Lutidine (0.2 mL, 1 mL) in a solution of 1,1,2,2,3,3-hexajuuteriopropane-1,3-diol (46 mg, 0.55 mmol) in DCM (1 mL) .64 mmol) and tosyl chloride (156 mg, 0.82 mmol, 1.5 eq) were added. The reaction mixture was stirred at 25 ° C. for 17 hours, diluted with DCM (15 mL), washed with 1N aqueous HCl (10 mL) and water (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (5-30% EtOAc in hexanes) to give the title compound (50 mg, 41%) as a colorless liquid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 99.72%, holding time = 2.75 minutes, MS calculated value: 236, MS measured value: 237.1 [M + H ⁺ ].

トリエチルアミン・３ＨＦ（０．０９mL、０．５５mmol）及びXtalFluor-E（登録商標）（９４mg、０．４１mmol）を、ジクロロメタン（５．０mL）に加えた。（１，１，２，２，３，３−ヘキサジュウテリオ−３−ヒドロキシ−プロピル）４−メチルベンゼンスルホナート（６５mg、０．２７mmol）を加え、反応混合物を２５℃で１７時間撹拌した。反応物を５％ ＮａＨＣＯ_３水溶液でクエンチした。層を分離し、水層をＤＣＭ（２×１０mL）で抽出した。合わせた有機層をブライン（１０mL）で洗浄し、乾燥し、濾過し、そして真空中で濃縮した。粗生成物を、シリカゲルカラムクロマトグラフィー（ヘキサン中５〜１０％ ＥｔＯＡｃ）により精製して、標記化合物（５０mg、８０％）を無色の液体として得、これを更に精製することなく次の反応工程で用いた。 b) (1,1,2,2,3,3-hexajuuterio-3-fluoro-propyl) 4-methylbenzenesulfonate

Triethylamine 3HF (0.09 mL, 0.55 mmol) and XtalFluor-E® (94 mg, 0.41 mmol) were added to dichloromethane (5.0 mL). (1,1,2,2,3,3-hexajuuterio-3-hydroxy-propyl) 4-methylbenzenesulfonate (65 mg, 0.27 mmol) was added, and the reaction mixture was stirred at 25 ° C. for 17 hours. The reaction was quenched with _{5% aqueous NaHCO 3 solution.} The layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (5-10% EtOAc in hexanes) to give the title compound (50 mg, 80%) as a colorless liquid, which was not further purified in the next reaction step. Using.

c) (1,1,2,2,3,3-hexajuterio-3-fluoro-propyl) 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclo Propyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] 2-ethyl-2-[(6-{[(1S, 1S,)) in butanoate DMF (1.5 mL) 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-yl) formamide] butanoic acid (Example 15k, 40 mg, 0.09 mmol) To the solution was _{added K 2} CO ₃ (39 mg, 0.29 mmol) and (1,1,2,2,3,3-hexajuterio-3-fluoro-propoxy) methylbenzene (45 mg, 0.19 mmol). .. The reaction mixture was stirred for 17 hours, quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (20-80% EtOAc in hexanes) to give the title compound (35 mg, 77%) as a colorless liquid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity was 83.98%, holding time = 3.21 minutes, MS calculated value: 487, MS measured value: 488.2 [M + H].

Example 20
3-Fluoropropyl 2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino ] -2-Vinyl-Puta-3-Enoart

３０mLの丸底フラスコ中で、２−エチル−２−（６−（（（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタン酸（実施例１５ｋ、３３８mg、８０２μmol、１当量）を、トルエン（１４mL）に溶解した。トリエチルアミン（８１mg、１１６μL、８０２μmol、１当量）及びＤＰＰＡ（２２１mg、１７３μL、８０２μmol、１当量）を加えた。反応混合物を周囲温度で２４時間撹拌し、水（２０mL）に注ぎ、そしてＡｃＯＥｔ（３×３０mL）で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（ＳｉＯ_２、１２０ｇ、ヘプタン中１０〜７０％ ＡｃＯＥｔ）により精製して、標記化合物（１７７mg、０．３９６mmol、４８％）をオフホワイトの固体として得た。
¹H NMR (600 MHz, CDCl₃):δ ppm 8.32 (s, 2 H, NH), 7.54 - 7.59 (d, ³J=7.9 Hz, 1 H, N_Py-C_q-CH-CH), 6.46 - 6.53 (d, ³J=7.9 Hz, 1 H, N_Py-C_q-CH), 4.09 - 4.30 (m, 8 H, m, O-CH₂, CH₂-N-CH₂, PO_3-O-CH₂, O-CH), 3.72 - 3.84 (m, 2 H, CH₂-N-CH₂), 3.23 (s, 3 H, O-CH₃), 2.35 - 2.51 (m, 2 H, N₃-CO-C_q-CH₂), 1.68 - 1.89 (m, 2 H, N₃-CO-C_q-CH₂), 1.24 - 1.34 (m, 2 H, CH-CH₂-CH), 0.74 (t, ³J=7.5 Hz, 6 H, N₃-CO-C_q-CH₂-CH₃), 0.63 - 0.72 (m, 2 H, CH-CH₂-CH)
ＨＲＭＳ（ＥＳＩ）：Ｃ_２１Ｈ_３０Ｎ_６Ｏ_５［Ｍ＋Ｈ］^＋の計算値＝４４７．２３０４； 実測値＝４４７．２２９６。 a) 2-Ethyl-2-(6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide) butanoyl azide

2-Ethyl-2-(6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) in a 30 mL round-bottom flask Picoline amide) butanoic acid (Example 15k, 338 mg, 802 μmol, 1 equivalent) was dissolved in toluene (14 mL). Triethylamine (81 mg, 116 μL, 802 μmol, 1 eq) and DPPA (221 mg, 173 μL, 802 μmol, 1 eq) were added. The reaction mixture was stirred at ambient temperature for 24 hours, poured into water (20 mL) and extracted with AcOEt (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (SiO ₂ , 120 g, 10-70% AcOEt in heptane) to give the title compound (177 mg, 0.396 mmol, 48%) as an off-white solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 8.32 (s, 2 H, NH), 7.54 --7.59 (d, ³ J = 7.9 Hz, 1 H, N _Py -C _q -CH-CH), 6.46 --6.53 (d, ³ J = 7.9 Hz, 1 H, N _Py -C _q -CH), 4.09 --4.30 (m, 8 H, m, O-CH ₂ , CH ₂ -N-CH ₂ , PO _3- O-CH ₂ , O-CH), 3.72 --3.84 (m, 2 H, CH ₂ -N-CH ₂ ), 3.23 (s, 3 H, O-CH ₃ ), 2.35 --2.51 (m, 2 H, N ₃ -CO-C _q -CH ₂ ), 1.68 --1.89 (m, 2 H, N ₃ -CO-C _q -CH ₂ ), 1.24 --1.34 (m, 2 H, CH-CH ₂ -CH), 0.74 (t, ³ J = 7.5 Hz, 6 H, N ₃ -CO-C _q -CH ₂ -CH ₃ ), 0.63 --0.72 (m, 2 H, CH-CH ₂ -CH)
HRMS (ESI): C ₂₁ H ₃₀ N ₆ O ₅ [M + H] ⁺ calculated value = 447.2304; measured value = 447.2296.

２５mLの丸底フラスコ中で、２−エチル−２−（６−（（（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド）ブタノイルアジド（１７７mg、０．３９６mmol、１当量）を、トルエン（１０．０mL）に溶解した。反応混合物を、３時間撹拌してすぐに１１０℃に加熱し、次に真空中で濃縮した。ＴＨＦ（３mL）及び３Ｎ ＮａＯＨ（７mL）を加えた。反応混合物を、撹拌してすぐに９０℃に１時間加熱し、水（１０mL）に注ぎ、そしてＡｃＯＥｔ（３×４０mL）で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、真空中で濃縮して、標記化合物（８５mg、０．２７７mmol、７０％）を淡橙色の油状物として得た。粗物質を更に精製することなく次の工程で用いた。
¹H NMR (600MHz, CDCl₃): δ ppm 8.18 (CO-NH₂), 7.74 (d, ³J=8.0 Hz, 1 H, N_Py-C_q-CH-CH), 6.56 (d, ³J=8.0 Hz, 1 H, N_Py-C_q-CH), 3.99 - 4.41 (m, 7 H, O-CH₂, CH₂-N-CH₂, O-CH, HO-CH₂), 3.95 - 4.00 (m, 2 H, CH₂-N-CH₂), 3.29 (m, 3 H, O-CH₃), 1.20 - 1.36 (CH-CH₂-CH), 0.54 - 0.79 (m, 2 H, CH-CH₂-CH)
ＭＳ（ＥＳＩ）：Ｃ_１５Ｈ_２１Ｎ_３Ｏ_４［Ｍ＋Ｈ］^＋の計算値＝３０８．１４； 実測値＝３０８．２０． b) 6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide

2-Ethyl-2- (6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) in a 25 mL round-bottom flask Picoline amide) butanoyl azide (177 mg, 0.396 mmol, 1 equivalent) was dissolved in toluene (10.0 mL). The reaction mixture was stirred for 3 hours and immediately heated to 110 ° C. and then concentrated in vacuo. THF (3 mL) and 3N NaOH (7 mL) were added. The reaction mixture was stirred and immediately heated to 90 ° C. for 1 hour, poured into water (10 mL) and extracted with AcOEt (3 x 40 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo to give the title compound (85 mg, 0.277 mmol, 70%) as a pale orange oil. The crude material was used in the next step without further purification.
¹ H NMR (600MHz, CDCl ₃ ): δ ppm 8.18 (CO-NH ₂ ), 7.74 (d, ³ J = 8.0 Hz, 1 H, N _Py -C _q -CH-CH), 6.56 (d, ³ J) = 8.0 Hz, 1 H, N _Py -C _q -CH), 3.99 --4.41 (m, 7 H, O-CH ₂ , CH ₂ -N-CH ₂ , O-CH, HO-CH ₂ ), 3.95- 4.00 (m, 2 H, CH ₂ -N-CH ₂ ), 3.29 (m, 3 H, O-CH ₃ ), 1.20 --1.36 (CH-CH ₂ -CH), 0.54 --0.79 (m, 2 H, CH-CH ₂ -CH)
MS (ESI): C ₁₅ H ₂₁ N ₃ O ₄ [M + H] ⁺ calculated value = 308.14; measured value = 308.20.

２５mLの丸底フラスコ中で、６−（（（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル）メトキシ）−５−（３−メトキシアゼチジン−１−イル）ピコリンアミド（８５mg、０．２７７mmol、１当量）を、メタノール（３mL）及び水（５mL）に溶解した。水酸化ナトリウム（５５mg、１．３８mmol、５当量）を加えた。反応混合物を、撹拌してすぐに８５℃に１２時間加熱し、水（１０mL）及び１Ｎ ＨＣｌ（３mL）に注ぎ、そしてＡｃＯＥｔ（３×２０mL）で抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（ＳｉＯ_２、１２ｇ、ヘプタン中４０〜１００％ ＡｃＯＥｔ）により精製して、標記化合物（６４mg、０．２０７mmol、７５％）を淡橙色の固体として得た。
¹H NMR (600 MHz, CDCl₃):δ ppm 7.72 (dd, ³J=7.9 Hz, ⁴J=2.9 Hz, 1 H, N_Py-C_q-CH-CH), 6.56 (d, ³J=7.9 Hz, 1 H, N_Py-C_q-CH), 3.99 - 4.41 (m, 7 H, O-CH₂, CH₂-N-CH₂, O-CH, HO-CH₂), 3.97 - 3.99 (m, 2 H, CH₂-N-CH₂), 3.28 (m, 3 H, O-CH₃), 1.18 - 1.32 (CH-CH₂-CH), 0.56 - 0.81 (m, 2 H, CH-CH₂-CH)
ＨＲＭＳ（ＥＳＩ）：Ｃ_１５Ｈ_２０Ｎ_２Ｏ_５［Ｍ＋Ｈ］^＋の計算値＝３０９．１３７９； 実測値＝３０９．１４５１。 c) 6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picolinic acid

In a 25 mL round bottom flask, 6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazetidine-1-yl) picoline amide (85 mg, 0. 277 mmol (1 eq) was dissolved in methanol (3 mL) and water (5 mL). Sodium hydroxide (55 mg, 1.38 mmol, 5 eq) was added. The reaction mixture was stirred and immediately heated to 85 ° C. for 12 hours, poured into water (10 mL) and 1N HCl (3 mL) and extracted with AcOEt (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (SiO ₂ , 12 g, 40-100% AcOEt in heptane) to give the title compound (64 mg, 0.207 mmol, 75%) as a pale orange solid.
¹ H NMR (600 MHz, CDCl ₃ ): δ ppm 7.72 (dd, ³ J = 7.9 Hz, ⁴ J = 2.9 Hz, 1 H, N _Py -C _q -CH-CH), 6.56 (d, ³ J = 7.9 Hz, 1 H, N _Py -C _q -CH), 3.99 --4.41 (m, 7 H, O-CH ₂ , CH ₂ -N-CH ₂ , O-CH, HO-CH ₂ ), 3.97 --3.99 (m, 2 H, CH ₂ -N-CH ₂ ), 3.28 (m, 3 H, O-CH ₃ ), 1.18 --1.32 (CH-CH ₂ -CH), 0.56 --0.81 (m, 2 H, CH -CH ₂ -CH)
HRMS (ESI): C ₁₅ H ₂₀ N ₂ O ₅ [M + H] ⁺ calculated value = 309.1379; actually measured value = 309.1451.

３−フルオロプロパン−１−オール（１．５５ｇ、１．６１mL、１９．８mmol、当量：１８）及び２−アミノ−２−ビニルブタ−３−エン酸塩酸塩（ＣＡＮ １８６５６９５−９１−５、１８０mg、１．１mmol、当量：１）を、丸底フラスコに加えた。二塩化硫黄（Sulfurous dichloride）（１．３１ｇ、７９８μL、１１mmol、当量：１０）を加えた。反応混合物を８０℃で１時間撹拌し、水（１０mL）に注ぎ、そしてＣＨ_２Ｃｌ_２（２×２０mL）で抽出した。有機層を合わせ、硫酸ナトリウムで乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、１２ｇ、ヘプタン中２０％〜７０％ ＡｃＯＥｔ）により精製して、標記化合物を無色の油状物として得た、ＬＣ−ＭＳ（ＵＶピーク面積／ＥＳＩ）９４％、１８７．１０８３ ［ＭＨ＋］。 d) 3-Fluoropropyl 2-amino-2-vinylbuta-3-enoart

3-Fluoropropane-1-ol (1.55 g, 1.61 mL, 19.8 mmol, equivalent: 18) and 2-amino-2-vinylbuta-3-enolate (CAN 186569-91-5, 180 mg, 180 mg, 1.1 mmol, equivalent: 1) was added to the round bottom flask. Sulfurous dichloride (1.31 g, 798 μL, 11 mmol, equivalent: 10) was added. The reaction mixture was stirred at 80 ° C. for 1 hour, poured into water (10 _{mL) and extracted with CH 2} Cl ₂ (2 x 20 mL). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 20% to 70% AcOEt in heptane) to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 94%, 187.1083 [MH +].

e) 3-Fluoropropyl 2- (1,2-ditrithioethyl) -2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine) -1-yl) pyridin-2-carbonyl] amino] -3,4-ditrithio-butanoate 6-(((1S, 2S) -2- (hydroxymethyl) cyclopropyl) methoxy) -5- (3-methoxyazeti) Din-1-yl) picolinic acid (19.8 mg, 64.1 μmol, equivalent: 0.8) and 3-fluoropropyl 2-amino-2-vinylbuta-3-enoate (15 mg, 80.1 μmol, equivalent: 1) Was dissolved in CH ₂ Cl ₂ (1.34 mL). N-Ethyl-N-isopropylpropan-2-amine (41.4 mg, 55.2 μL, 320 μmol, equivalent: 4), followed by 1- (bis (dimethylamino) methylene) -1H- [1,2,3] Triazolo [4,5-b] pyridine-1-ium 3-oxide hexafluorophosphate (V) (36.6 mg, 96.1 μmol, equivalent: 1.2) was added. The reaction mixture was stirred at ambient temperature for 1 hour, poured into water (10 _{mL) and extracted with CH 2} Cl ₂ (4 x 20 mL). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 20% to 70% AcOEt in heptane) to give the title compound as a colorless oil, LC-MS (UV peak area / ESI) 98%, 478.2399 [MH +].

２mlのジューテリウム化フラスコ中で、３−フルオロプロピル ２−［［６−［［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ］−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−カルボニル］アミノ］−２−ビニル−ブタ−３−エノアート（１．０mg、２．０９μmol、１．０当量）及びＰｄ／Ｃ（１０％）（１．１１mg、１．０５μmol、０．５当量）を、ジメチルホルムアミド（０．５ml）に懸濁した。フラスコをジューテリウムマニホールド（RC-TRITEC）に取り付け、凍結−ポンプ−解凍により脱気した。ジューテリウムガスを導入し、黒色の懸濁液をジューテリウムの雰囲気下、６００mbarで２．５時間激しく撹拌した。黒色の懸濁液を１７mmのチタンＨＰＬＣフィルター（０．４５μm、ＰＴＦＥ）で濾過し、メタノール（３×２ml）で洗浄した。無色の溶液を濃縮して、ＨＰＬＣ（SunFire C18、５μm、４．６×２５０mm； 溶離液：アセトニトリル［Ａ］、水中５％アセトニトリル［Ｂ］； 勾配：１０％［Ａ］、９０％［Ｂ］〜９９％［Ａ］、１２分で１％［Ｂ］、３分間保持、次に５分間初期条件に戻した）により測定したとおり、純度＞９８％で１mgの標記化合物を得た。ＭＳ ｍ／ｚ：４８３．４［Ｍ（^２Ｈ）＋Ｈ］^＋（４％）、４８４．４［Ｍ（^２Ｈ_２）＋Ｈ］^＋（９％）、４８５．４［Ｍ（^２Ｈ_３）＋Ｈ］^＋（１４％）、４８６．４［Ｍ（^２Ｈ_４）＋Ｈ］^＋（２７％）、４８７．４［Ｍ（^２Ｈ_５）＋Ｈ］^＋（２１％）、４８８．４［Ｍ（^２Ｈ_６）＋Ｈ］^＋（１８％）、４８９．４ ［Ｍ（^２Ｈ_７）＋Ｈ］^＋（７％）。 Example 21
3-Fluoropropyl 3,4-dijuuterio-2- (1,2-dijuuterioethyl) -2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5] -(3-Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate

In a 2 ml juteriumized flask, 3-fluoropropyl 2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carbonyl] amino] -2-vinyl-but-3-enoate (1.0 mg, 2.09 μmol, 1.0 equivalent) and Pd / C (10%) (1.11 mg, 1.05 μmol, 0.5 equivalent) was suspended in dimethylformamide (0.5 ml). The flask was attached to a juterium manifold (RC-TRITEC) and degassed by freezing-pump-thawing. Juterium gas was introduced and the black suspension was vigorously stirred at 600 mbar for 2.5 hours in a Juterium atmosphere. The black suspension was filtered through a 17 mm titanium HPLC filter (0.45 μm, PTFE) and washed with methanol (3 x 2 ml). The colorless solution is concentrated and HPLC (SunFire C18, 5 μm, 4.6 × 250 mm; eluent: acetonitrile [A], 5% acetonitrile in water [B]; gradient: 10% [A], 90% [B]. As measured by ~ 99% [A], 1% [B] at 12 minutes, retention for 3 minutes, then returned to initial conditions for 5 minutes), 1 mg of the title compound was obtained with a purity of> 98%. MS m / z: 483.4 [M ( ² H) + H] ⁺ (4%), 484.4 [M ( ² H ₂ ) + H] ⁺ (9%), 485.4 [M ( ² H ₃ )) + H] ⁺ (14%), 486.4 [M ( ² H ₄ ) + H] ⁺ (27%), 487.4 [M ( ² H ₅ ) + H] ⁺ (21%), 488.4 [M (M) ² H ₆ ) + H] ⁺ (18%), 489.4 [M ( ² H ₇ ) + H] ⁺ (7%).

Example 22
(Rac) -trans-3-fluoropropyl 2-[[6-[[-2- (benzyloxymethyl) cyclopropyl] methoxy] -5- (3-hydroxyazetidine-1-yl) pyridin-2-carbonyl ] Amino] -2-ethyl-butanoart

ＤＭＦ（３５mL）中の５−ブロモ−６−クロロ−ピリジン−２−カルボン酸（２．０ｇ、８．５mmol）の溶液を、アルゴン下で０℃に冷却した。ＮａＨ（６０％油性懸濁液、１．０１ｇ、２５．４mmol）を加え、混合物を０℃で２０分間撹拌した。ＤＭＦ（５mL）中の（rac）−trans−［−２−［（ベンジルオキシ）メチル］シクロプロピル］メタノール（２．２７７ｇ、１１．８mmol）の溶液を、ゆっくりと加えた。混合物を８０℃に３時間加熱し、２５℃に冷却し、そして２Ｎ ＨＣｌ水溶液でｐＨを約２に調整した。水を加え（４００mL）、混合物をＥｔＯＡｃ（３×２００mL）で抽出した。合わせた有機層をブライン（１５０mL）で洗浄し、乾燥し、濾過し、真空中で濃縮して、粗標記化合物を淡黄色のガム状物として得、これを更に精製することなく次の工程で用いた。 a) (Rac) -trans-6- (-2-benzyloxymethyl-cyclopropylmethoxy) -5-bromo-pyridin-2-carboxylic acid

A solution of 5-bromo-6-chloro-pyridine-2-carboxylic acid (2.0 g, 8.5 mmol) in DMF (35 mL) was cooled to 0 ° C. under argon. NaH (60% oily suspension, 1.01 g, 25.4 mmol) was added and the mixture was stirred at 0 ° C. for 20 minutes. A solution of (rac) -trans- [-2-[(benzyloxy) methyl] cyclopropyl] methanol (2.277 g, 11.8 mmol) in DMF (5 mL) was added slowly. The mixture was heated to 80 ° C. for 3 hours, cooled to 25 ° C. and adjusted to pH about 2 with 2N HCl aqueous solution. Water was added (400 mL) and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (150 mL), dried, filtered and concentrated in vacuo to give the crudely labeled compound as a pale yellow gum, which was not further purified in the next step. Using.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] This mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN], and in 10% [10 mM NH ₄ OAc in water] and 90% [CH _{3 CN] in 3.0 minutes for up to 4 minutes.} Finally, it returned to the initial condition in 5 minutes). Purity was 71.32%, retention time = 2.67 min, MS calcd: 392, MS ^{Found: 392.1 [M-H -]} .

ＤＭＦ（１５mL）中の（rac）−trans−６−（−２−ベンジルオキシメチル−シクロプロピルメトキシ）−５−ブロモ−ピリジン−２−カルボン酸（３．３ｇ、８．４mmol）の溶液に、ＤＩＰＥＡ（５．９mL、３３．７mmol）、エチル ２−アミノ−２−エチルブタノアート塩酸塩（１．６４６ｇ、８．４mmol）及びＴＢＴＵ（２．７０１ｇ、８．４mmol）を加えた。反応混合物を２５℃で１６時間撹拌し、水（２００mL）に注ぎ、そしてＥｔＯＡｃ（３×１００mL）で抽出した。合わせた有機層をブライン（１００mL）で洗浄し、乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘキサン中０％〜５％ ＡｃＯＥｔ）により精製して、標記化合物（２．９５ｇ、６６％）を無色のガム状物として得た。 b) (Rac) -trans-ethyl 2-[[6-[[-2- (benzyloxymethyl) cyclopropyl] methoxy] -5-bromo-pyridin-2-carbonyl] amino] -2-ethyl-butanoate

In a solution of (rac) -trans-6- (-2-benzyloxymethyl-cyclopropylmethoxy) -5-bromo-pyridin-2-carboxylic acid (3.3 g, 8.4 mmol) in DMF (15 mL), DIPEA (5.9 mL, 33.7 mmol), ethyl 2-amino-2-ethylbutanoate hydrochloride (1.646 g, 8.4 mmol) and TBTU (2.701 g, 8.4 mmol) were added. The reaction mixture was stirred at 25 ° C. for 16 hours, poured into water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% -5% AcOEt in hexanes) to give the title compound (2.95 g, 66%) as a colorless gum.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 96.75%, holding time = 4.65 minutes, MS calculated value: 533, MS measured value: 534.8 [M + H ⁺ ].

ＫＯＨ（２８２mg、２．３４mmol）を、ＴＨＦ（４mL）、ＭｅＯＨ（４．４mL）及び水（４．０mL）中の（rac）−trans−エチル ２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−ブロモピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（２５０mg、０．４６mmol）の溶液に加えた。混合物を９０℃に１８時間加熱した。有機溶媒を減圧下で除去した。残留水相のｐＨを１Ｍ ＨＣｌを用いて２に調整した。ＥｔＯＡｃ（３×２５mL）での抽出が続いた。合わせた有機層をブライン（１×３０mL）で洗浄し、乾燥し、濾過し、減圧下で乾燥させて、標記化合物（２３０mg、９７％）を淡黄色の粘着性の塊として得た。 c) (Rac) -trans-2-[[6-[[-2- (benzyloxymethyl) cyclopropyl] methoxy] -5-bromo-pyridin-2-carbonyl] amino] -2-ethyl-butanoic acid

KOH (282 mg, 2.34 mmol) in THF (4 mL), MeOH (4.4 mL) and water (4.0 mL) with (rac) -trans-ethyl 2-[(6-{[-2-[(6-{[-2-[(). Benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-yl) formamide] -2-ethylbutanoate (250 mg, 0.46 mmol) was added to the solution. The mixture was heated to 90 ° C. for 18 hours. The organic solvent was removed under reduced pressure. The pH of the residual aqueous phase was adjusted to 2 with 1M HCl. Extraction with EtOAc (3 x 25 mL) was followed. The combined organic layers were washed with brine (1 x 30 mL), dried, filtered and dried under reduced pressure to give the title compound (230 mg, 97%) as a pale yellow sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 99.03%, holding time = 2.8 minutes, MS calculated value: 505, MS measured value: 503.3 [M + H ⁺ ].

丸底フラスコ中で、Ｋ_２ＣＯ_３（２３０mg，１．６６mmol）をＤＭＦ（８mL）に懸濁した。（Rac）−trans−２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−ブロモピリジン−２−イル）ホルムアミド］−２−エチルブタン酸（２８０mg、０．５５mmol）及び１−ヨード−３−フルオロ−プロパン（３１３mg、１．６６mmol）を加えた。混合物を２５℃で２時間撹拌した。氷冷水を加え、混合物をＥｔＯＡｃ（３×５０mL）で抽出した。合わせた有機層をブライン（２０mL）で洗浄し、乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘキサン中０％〜３０％ ＡｃＯＥｔ）により精製して、標記化合物（２２５mg、７２％）を無色の粘着性の塊として得た。 d) (Rac) -trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-yl) formamide] -2- Ethylbutanoart

_{K 2} CO ₃ (230 mg, 1.66 mmol) was suspended in DMF (8 mL) in a round bottom flask. (Rac) -trans-2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-yl) formamide] -2-ethylbutanoic acid (280 mg, 0) .55 mmol) and 1-iodo-3-fluoro-propane (313 mg, 1.66 mmol) were added. The mixture was stirred at 25 ° C. for 2 hours. Ice-cold water was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% AcOEt in hexanes) to give the title compound (225 mg, 72%) as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 99.38%, holding time = 2.41 minutes, MS calculated value: 565, MS measured value: 565.3 [M + H].

e) 3-Fluoropropyl 2-amino-2-vinylbuta-3-enoate (rac) -trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy) methyl) in toluene (5 mL)) ] Cyclopropyl] methoxy} -5-bromopyridin-2-yl) formamide] -2-ethylbutanoate (225 mg, 0.39 mmol) in a solution of azetidine-3-ol HCl (87 mg, 0.79 mmol) And cesium carbonate (519 mg, 1.59 mmol) was added. The mixture was degassed with argon for 10 minutes. BINAP (100 mg, 0.16 mmol) and Pd (II) acetate (36 mg, 0.16 mmol) were added and the mixture was heated at 110 ° C. for 3 hours. The reaction mixture was diluted with EtOAc (30 mL), filtered through a bed of Celite, and the defective Celite was washed with EtOAc (30 mL). The solvent was removed in vacuo. The crude material was purified by flash chromatography (silica gel, 10% to 70% EtOAc in heptane) followed by SFC purification to give the title compound (130 mg, 59%) as a yellowish sticky solid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity was 98.28%, holding time = 3.63 minutes, MS calculated value: 557, MS measured value: 558.0 [M + H ⁺ ].

Example 23
3- (p-Tolylsulfonyloxy) propyl 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino] Butanoart

ＤＣＭ（５mL）中のプロパン−１，３−ジオール（５００mg、６．５８mmol）の溶液に、２，６−ルチジン（２．３mL、１９．７４mmol）及び塩化トシル（２．５０８ｇ、１３．１６mmol）を加えた。反応混合物を２５℃で１７時間撹拌し、ＤＣＭ（５０mL）で希釈し、１ ＨＣｌ水溶液、水（２０mL）で洗浄し、乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘプタン中５％〜３０％ ＥｔＯＡｃ）により精製して、標記化合物（１０００mg、４０％）を白色の固体として得た。 a) 3-{[(4-Methylbenzene) sulfonyl] oxy} propyl 4-methylbenzene-1-sulfonate

2,6-Lutidine (2.3 mL, 19.74 mmol) and tosyl chloride (2.508 g, 13.16 mmol) in a solution of propane-1,3-diol (500 mg, 6.58 mmol) in DCM (5 mL). Was added. The reaction mixture was stirred at 25 ° C. for 17 hours, diluted with DCM (50 mL), washed with 1 HCl aqueous solution, water (20 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 5% -30% EtOAc in heptane) to give the title compound (1000 mg, 40%) as a white solid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 97.88%, holding time = 3.56 minutes, MS calculated value: 384, MS measured value: 402.1 [M + NH ₄ ⁺ ].

b) 3- (p-tolylsulfonyloxy) propyl 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine) -1-yl) pyridin-2-carbonyl] amino] 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy}-in butanoate DMF (5 mL))- In a solution of 5- (3-methoxyazetidine-1-yl) pyridin-2-yl) formamide] butanoic acid (Example 15k, 260 mg, 0.62 mmol), K ₂ CO ₃ (256 mg, 1.85 mmol) and 3-{[(4-Methylbenzene) sulfonyl] oxy} propyl 4-methylbenzene-1-sulfonate (711 mg, 1.85 mmol) was added. The reaction mixture was stirred at 25 ° C. for 16 hours, poured into water, quenched with 1N aqueous HCl and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (30 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20% -80% EtOAc in heptane) to give the title compound (255 mg, 65%) as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 90.68%, holding time = 3.48 minutes, MS calculated value: 633, MS measured value: 634.4 [M + H ⁺ ].

Example 24
[1,1,2,2,3,3-hexajuuterio-3- (p-tolylsulfonyloxy) propyl] 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxy) Methyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate

ＤＣＭ（１mL）中のプロパン−１，３−ジオール（ｄ_６）（７３mg、０．８７mmol）の溶液に、２，６−ルチジン（０．５mL、４．３４mmol）及び塩化トシル（４９６mg、２．６mmol、３当量）を加えた。反応混合物を２５℃で１７時間撹拌し、ＤＣＭ（２０mL）で希釈し、１Ｎ ＨＣｌ水溶液及び水（１０mL）で洗浄し、乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘキサン中５％〜３０％ ＥｔＯＡｃ）により精製して、標記化合物（２０５mg、６１％）を白色の固体として得た。 a) [1,1,2,2,3,3-hexajuuterio-3- (p-tolylsulfonyloxy) propyl] 4-methylbenzenesulfonate

2.6-Lutidine (0.5 mL, 4.34 mmol) and tosyl chloride (496 mg, 2.) In a solution of propane-1,3-diol (d _{6) (73 mg, 0.87 mmol) in DCM (1 mL).} 6 mmol (3 equivalents) was added. The reaction mixture was stirred at 25 ° C. for 17 hours, diluted with DCM (20 mL), washed with 1N aqueous HCl and water (10 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 5% to 30% EtOAc in hexanes) to give the title compound (205 mg, 61%) as a white solid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 99.84%, holding time = 3.48 minutes, MS calculated value: 390, MS measured value: 408.1 [M + NH ₄ ⁺ ].

b) [1,1,2,2,3,3-hexajuterio-3- (p-tolylsulfonyloxy) propyl] 2-ethyl-2-[[6-[[(1S, 2S) -2- (Hydroxymethyl) Cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] Butanoate 2-ethyl-2-[(6--) in DMF (5.0 mL) {[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-yl) formamide] Butanoic acid (Example 15k, 50 mg, In a solution of 0.12 mmol), K ₂ CO ₃ (49 mg, 0.35 mmol) and [1,1,2,2,3,3-hexajuuterio-3- (p-tolylsulfonyloxy) propyl] 4- Methylbenzene sulfonate (93 mg, 0.24 mmol) was added. The reaction mixture was stirred at 25 ° C. for 17 hours, quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 30% -80% EtOAc in hexanes) to give the title compound (50 mg, 67%) as a colorless liquid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 95.50%, holding time = 3.47 minutes, MS calculated value: 639, MS measured value: 640.3 [M + H ⁺ ].

ＤＭＦ（５mL）中の２−エチル−２−［（６−｛［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］ブタン酸（実施例１５ｋ、６０mg、０．１４mmol）の溶液に、Ｋ_２ＣＯ_３（５９mg、０．４３mmol）及び１−ブロモ−４−フルオロブタン（６６mg、０．４３mmol）を加えた。反応混合物を２５℃で２時間撹拌し、水に注ぎ、１Ｎ ＨＣｌ水溶液でクエンチし、そしてＥｔＯＡｃ（３×１５mL）で抽出した。合わせた有機層をブライン（１０mL）で洗浄し、乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘキサン中１０％〜４０％ ＥｔＯＡｃ）により精製して、標記化合物（２６mg、３７％）を無色の液体として得た。 Example 25
4-Fluorobutyl 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] Amino] Butanoart

2-Ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine) in DMF (5 mL) _{-2-yl) Formamide] K 2} CO ₃ (59 mg, 0.43 mmol) and 1-bromo-4-fluorobutane (66 mg, 0.43 mmol) in a solution of butanoic acid (Example 15 k, 60 mg, 0.14 mmol). ) Was added. The reaction mixture was stirred at 25 ° C. for 2 hours, poured into water, quenched with 1N aqueous HCl and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10% -40% EtOAc in hexanes) to give the title compound (26 mg, 37%) as a colorless liquid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 92.73%, holding time = 1.39 minutes, MS calculated value: 495, MS measured value: 495.6 [M + H ⁺ ].

ＤＣＭ（５．０mL）中の２−エチル−２−［（６−｛［（１Ｓ，２Ｓ）−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝−５−（３−メトキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］ブタン酸（実施例１５ｋ、３０mg，０．０６mmol）の溶液に、ＥＤＣ・ＨＣｌ（１８mg、０．０９mmol）及びＨＯＢｔ（８mg、０．０６mmol）を加えた。反応混合物を２５℃で３０分間撹拌した。（２Ｓ）−２−アミノ−４−メチルペンタン−１−オール（１１mg、０．０９mmol）及びＤＩＰＥＡ（０．０２mL、０．０９mmol）を加えた。混合物を２５℃で１２時間撹拌し、ＤＣＭ（１０mL）で希釈し、水（２×５mL）及びブライン（５mL）で洗浄した。合わせた抽出物を乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘキサン中０％〜７０％ ＥｔＯＡｃ）により精製して、標記化合物（１４mg、４５％）を無色の粘着性の塊として得た。 Example 26
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -6-[[(1S, 2S) -2- (hydroxymethyl) cyclo Propyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridine-2-carboxamide

2-Ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) in DCM (5.0 mL)) ) Pyridine-2-yl) formamide] To a solution of butanoic acid (Example 15k, 30 mg, 0.06 mmol) was added EDC HCl (18 mg, 0.09 mmol) and HOBt (8 mg, 0.06 mmol). The reaction mixture was stirred at 25 ° C. for 30 minutes. (2S) -2-Amino-4-methylpentane-1-ol (11 mg, 0.09 mmol) and DIPEA (0.02 mL, 0.09 mmol) were added. The mixture was stirred at 25 ° C. for 12 hours, diluted with DCM (10 mL) and washed with water (2 x 5 mL) and brine (5 mL). The combined extracts were dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give the title compound (14 mg, 45%) as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 78.15%, holding time = 3.06 minutes, MS calculated value: 520, MS measured value: 521.2 [M + H ⁺ ].

Example 27
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6- [ [(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridine-2-carboxamide or N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl- Butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridin-2-carboxamide

トルエン（１２mL）中の（rac）−trans−エチル ２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−ブロモピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（実施例２２ｂ、２５０mg、０．４７mmol）の溶液に、３−フルオロアゼチジン（fluorozetidine）塩酸塩（７８mg、０．７０mmol）及び炭酸セシウム（４５８mg、１．４１mmol）を加えた。混合物をアルゴンで１０分間脱気した。Rac−ＢＩＮＡＰ（５８mg、０．０９mmol）及びＰｄ（II）アセタート（２１mg、０．０９mmol）を加え、混合物を１１０℃に３時間加熱した。反応混合物をＥｔＯＡｃ（３０mL）で希釈し、セライトベッドで濾過し、そしてベッドをＥｔＯＡｃ（３０mL）で洗浄した。濾液を真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘキサン中１０％〜２０％ ＥｔＯＡｃ）により精製して、標記化合物（２０５mg、８３％）を褐色の液体として得た。 a) (Rac) -trans-ethyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl) pyridin-2- Il) formamide] -2-ethylbutanoart

(Rac) -trans-ethyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-bromopyridin-2-yl) formamide] -2 in toluene (12 mL) -To a solution of ethylbutanoate (Example 22b, 250 mg, 0.47 mmol) was added 3-fluorozetidine hydrochloride (78 mg, 0.70 mmol) and cesium carbonate (458 mg, 1.41 mmol). .. The mixture was degassed with argon for 10 minutes. Rac-BINAP (58 mg, 0.09 mmol) and Pd (II) acetate (21 mg, 0.09 mmol) were added and the mixture was heated to 110 ° C. for 3 hours. The reaction mixture was diluted with EtOAc (30 mL), filtered through a Celite bed, and the bed was washed with EtOAc (30 mL). The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10% to 20% EtOAc in hexanes) to give the title compound (205 mg, 83%) as a brown liquid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 98.26%, holding time = 4.21 minutes, MS calculated value: 527, MS measured value: 527.9 [M + H ⁺ ].

２５mLの丸底フラスコ中で、（rac）−trans−エチル ２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−フルオロアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（２９０mg、０．５５mmol）を、ＴＨＦ（２．５mL）、ＭｅＯＨ（２．８mL）及び水（２．５mL）と合わせて、淡黄色の溶液を得た。ＫＯＨペレット（１５４mg、２．７５mmol）を加えた。混合物を９０℃に１８時間加熱した。有機溶媒を減圧下で除去した。水相を水（３０mL）で希釈し、ジエチルエーテル（２×１０mL）で抽出した。有機部分を廃棄し、水相をｐＨ約２（１Ｍ ＨＣｌ）に調整し、そしてＥｔＯＡｃ（３×２５mL）で抽出した。合わせた有機層をブライン（１×２０mL）で洗浄し、乾燥し、濾過し真空中で、濃縮して、標記化合物（２６０mg、９５％）を褐色の粘着性の塊として得た。 b) (Rac) -trans-2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl) pyridin-2-yl) ) Formamide] -2-ethylbutanoic acid

In a 25 mL round bottom flask, (rac) -trans-ethyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-) Il) Pyridine-2-yl) formamide] -2-ethylbutanoate (290 mg, 0.55 mmol) in combination with THF (2.5 mL), MeOH (2.8 mL) and water (2.5 mL). A pale yellow solution was obtained. KOH pellets (154 mg, 2.75 mmol) were added. The mixture was heated to 90 ° C. for 18 hours. The organic solvent was removed under reduced pressure. The aqueous phase was diluted with water (30 mL) and extracted with diethyl ether (2 x 10 mL). The organic moiety was discarded, the aqueous phase was adjusted to pH about 2 (1M HCl) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (1 x 20 mL), dried, filtered and concentrated in vacuo to give the title compound (260 mg, 95%) as a brown sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 100%, holding time = 2.70 minutes, MS calculated value: 497, MS measured value: 498.4 [M + H ⁺ ].

ＤＣＭ（１２mL）中の（rac）−trans−２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−フルオロアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチルブタン酸（１８０mg、０．３６mmol）の溶液に、ＥＤＣ・ＨＣｌ（１０４mg、０．５４mmol）及びＨＯＢｔ（４９mg、０．３６mmol）を加えた。反応混合物を２５℃で３０分間撹拌した。（Ｓ）−２−アミノ−４−メチル−ペンタン−１−オール（６３mg、０．５４mmol）及びＤＩＰＥＡ（０．０９mL、０．５４mmol）を加えた。混合物を２５℃で１２時間撹拌し、ＤＣＭ（３０mL）で希釈し、そして水（２０mL）及びブライン（１０mL）で洗浄した。合わせた抽出物を乾燥し、濾過し、そして真空中で濃縮した。粗物質を、フラッシュクロマトグラフィー（シリカゲル、ヘキサン中０％〜７０％ ＥｔＯＡｃ）により精製して、標記化合物（１６０mg、７４％）を粘着性固体として得た。 c) trans-2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl) pyridin-2-yl) formamide]- 2-Ethyl-N-[(2S) -1-hydroxy-4-methylpentane-2-yl] butaneamide

(Rac) -trans-2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl) pyridine) in DCM (12 mL) -2-yl) Formamide] EDC / HCl (104 mg, 0.54 mmol) and HOBt (49 mg, 0.36 mmol) were added to a solution of -2-ethylbutanoic acid (180 mg, 0.36 mmol). The reaction mixture was stirred at 25 ° C. for 30 minutes. (S) -2-Amino-4-methyl-pentane-1-ol (63 mg, 0.54 mmol) and DIPEA (0.09 mL, 0.54 mmol) were added. The mixture was stirred at 25 ° C. for 12 hours, diluted with DCM (30 mL) and washed with water (20 mL) and brine (10 mL). The combined extracts were dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give the title compound (160 mg, 74%) as a sticky solid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 89.65%, holding time = 3.77 minutes, MS calculated value: 598, MS measured value: 599.1 [M + H ⁺ ].

d) N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6 -[[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridine-2-carboxamide or N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-) Methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridin-2-carboxamide EtOAc Trans-2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl)) in (6 mL) and methanol (0.6 mL) ) Pyridin-2-yl) formamide] -2-ethyl-N-[(2S) -1-hydroxy-4-methylpentane-2-yl] butaneamide (160 mg, 0.27 mmol) is degassed for 10 minutes. bottom. Pd-C (10%) (80 mg) was added and degassing was continued for another 2 minutes. The mixture is then placed under a hydrogen atmosphere at balloon pressure, stirred at 25 ° C. for 17 hours, filtered through a Celite bed, concentrated in vacuo and crude trans-2-ethyl-2-{[5- (3). −Fluoroazetidine-1-yl) -6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} pyridin-2-yl] formamide} -N-[(2S) -1-hydroxy-4-methylpentane -2-yl] Butanamide (130 mg, 86%) was obtained as a colorless gum. The crude product was prepared by preparative chiral HPLC (column: Chiralpak IE (250 x 4.6 mm), 5i; mobile phase: hexane / EtOH / DEA: 90/10 / 0.1; flow velocity: 1.0 mL / min). Purification gave the title compound (27 mg, 20%, 100% ee).

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30 in 1.5 minutes. This mobile phase composition was retained in% [CH3CN] for an additional 3.0 minutes, 10% [10 mM NH4OAc in water] and 90% [CH3CN] for up to 4 minutes, and finally returned to the initial conditions in 5 minutes. ). The purity is 97.62%, holding time = 3.09 minutes, MS calculated value: 508, MS measured value: 509.1 [M + H ⁺ ].

ＥｔＯＡｃ（６mL）及びメタノール（０．６mL）中のtrans−２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−フルオロアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチル−Ｎ−［（２Ｓ）−１−ヒドロキシ−４−メチルペンタン−２−イル］ブタンアミド（１６０mg、０．２７mmol）の溶液を、１０分間脱気した。Ｐｄ−Ｃ（１０％）（８０mg）を加え、脱気を更に２分間続けた。次に、混合物をバルーン圧力で水素雰囲気下に置き、２５℃で１７時間撹拌し、セライトベッドで濾過し、真空中で濃縮して、粗trans−２−エチル−２−｛［５−（３−フルオロアゼチジン−１−イル）−６−｛［−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝ピリジン−２−イル］ホルムアミド｝−Ｎ−［（２Ｓ）−１−ヒドロキシ−４−メチルペンタン−２−イル］ブタンアミド（１３０mg、８６％）を無色のガム状物として得た。粗生成物を、分取キラルＨＰＬＣ（カラム：Chiralpak IE（２５０×４．６mm）、５i； 移動相：ヘキサン／ＥｔＯＨ／ＤＥＡ：９０／１０／０．１； 流速：１．０mL／分）により精製して、標記化合物を得た（２７mg、２０％、８９％ ｅｅ）。 Example 28
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6- [ [(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridine-2-carboxamide or N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl- Butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6-[[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridin-2-carboxamide

Trans-2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-) in EtOAc (6 mL) and methanol (0.6 mL) Il) Pyridine-2-yl) formamide] -2-ethyl-N-[(2S) -1-hydroxy-4-methylpentane-2-yl] butaneamide (160 mg, 0.27 mmol) solution was removed for 10 minutes. I was worried. Pd-C (10%) (80 mg) was added and degassing was continued for another 2 minutes. The mixture is then placed under a hydrogen atmosphere at balloon pressure, stirred at 25 ° C. for 17 hours, filtered through a Celite bed, concentrated in vacuo and crude trans-2-ethyl-2-{[5- (3). −Fluoroazetidine-1-yl) -6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} pyridin-2-yl] formamide} -N-[(2S) -1-hydroxy-4-methylpentane -2-yl] Butanamide (130 mg, 86%) was obtained as a colorless gum. The crude product was prepared by preparative chiral HPLC (column: Chiralpak IE (250 x 4.6 mm), 5i; mobile phase: hexane / EtOH / DEA: 90/10 / 0.1; flow velocity: 1.0 mL / min). Purification gave the title compound (27 mg, 20%, 89% ee).

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 90% [10 mM NH4OAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30 in 1.5 minutes. This mobile phase composition was retained in% [CH3CN] for an additional 3.0 minutes, 10% [10 mM NH4OAc in water] and 90% [CH3CN] for up to 4 minutes, and finally returned to the initial conditions in 5 minutes. ). The purity is 95.79%, holding time = 3.09 minutes, MS calculated value: 508, MS measured value: 509.3 [M + H ⁺ ].

Example 29
3-Fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} pyridine-2 -Il] formamide} butanoate or 3-fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1S, 2S) -2- (hydroxymethyl) cyclo Propyl] methoxy} pyridin-2-yl] formamide} butanoart

ＤＭＦ（１０mL）中の（rac）−trans−２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−フルオロアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチルブタン酸（実施例２７ｂ、１７０mg、０．３４mmol）の溶液に、Ｋ_２ＣＯ_３（１４１mg、１．０２mmol）及び１−フルオロ−３−ヨード−プロパン（１９２mg、１．０２mmol）を加えた。混合物を２５℃で２時間撹拌し、水（１００mL）で希釈し、そしてＥｔＯＡｃ（３×５０mL）で抽出した。合わせた有機層をブライン（３０mL）で洗浄し、乾燥し、濾過し、真空中で濃縮して、標記化合物（１７０mg）を黄色のガム状物として得、これを更に精製することなく次の反応工程で用いた。 a) (Rac) -trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl) pyridine -2-yl) formamide] -2-ethylbutanoart

(Rac) -trans-2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl) pyridine) in DMF (10 mL) 2-yl) formamide] -2-ethylbutanoic acid (example 27b, 170 mg, to a solution of _{0.34mmol), K 2 CO 3 (} 141mg, 1.02mmol) and 1-fluoro-3-iodo - propane (192 mg , 1.02 mmol) was added. The mixture was stirred at 25 ° C. for 2 hours, diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried, filtered and concentrated in vacuo to give the title compound (170 mg) as a yellow gum, which was then reacted without further purification. Used in the process.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 63.82%, holding time = 4.02 minutes, MS calculated value: 559, MS measured value: 560.1 [M + H ⁺ ].

b) 3-Fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} pyridine -2-yl] formamide} butanoate or 3-fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1S, 2S) -2- (hydroxymethyl) ) Cyclopropyl] methoxy} pyridin-2-yl] formamide} Butanoart in EtOAc (6 mL) and methanol (0.6 mL) (rac) -trans-3-fluoropropyl 2-[(6-{[-2- [2] A solution of (benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-fluoroazetidine-1-yl) pyridin-2-yl) formamide] -2-ethylbutanoate (160 mg, 0.29 mmol) Degassed for 10 minutes. Pd-C (10%, 80 mg) was added and degassing was continued for another 2 minutes. The mixture was placed under a hydrogen atmosphere at balloon pressure and stirred at 25 ° C. for 17 hours. The reaction mixture is filtered through a Celite bed and concentrated in vacuo to crude (rac) -trans-3-fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6. -{[-2- (Hydroxymethyl) cyclopropyl] methoxy} pyridin-2-yl] formamide} butanoate (140 mg) was obtained as a colorless gum. Preparative chiral HPLC (column: Chilarpak IC (250 x 4.6 mm), 5i; mobile phase: hexane / EtOH / isopropylamine: 80/20 / 0.1; flow velocity: 1.0 mL / min) The title compound (34 mg, 24%) was obtained as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 98.47%, holding time = 3.26 minutes, MS calculated value: 469, MS measured value: 470.1 [M + H ⁺ ].

ＥｔＯＡｃ（６mL）及びメタノール（０．６mL）中の（rac）−trans−３−フルオロプロピル ２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−フルオロアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（１６０mg、０．２９mmol）の溶液を、１０分間脱気した。Ｐｄ−Ｃ（１０％、８０mg）を加え、脱気を更に２分間続けた。混合物をバルーン圧力で水素雰囲気下に置き、２５℃で１７時間撹拌した。反応混合物をセライトベッドで濾過し、真空中で濃縮して、粗（rac）−trans−３−フルオロプロピル ２−エチル−２−｛［５−（３−フルオロアゼチジン−１−イル）−６−｛［−２−（ヒドロキシメチル）シクロプロピル］メトキシ｝ピリジン−２−イル］ホルムアミド｝ブタノアート（１４０mg）を無色のガム状物として得た。粗生成物を、分取キラルＨＰＬＣ（カラム：Chiralpak IC（２５０×４．６mm）、５i； 移動相：ヘキサン／ＥｔＯＨ／イソプロピルアミン：８０／２０／０．１； 流速：１．０mL／分）により精製して、標記化合物（３７mg、２６％）を無色の粘着性の塊として得た。 Example 30
3-Fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} pyridine-2 -Il] formamide} butanoate or 3-fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1R, 2R) -2- (hydroxymethyl) cyclo Propyl] methoxy} pyridin-2-yl] formamide} butanoart

(Rac) -trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-(in EtOAc (6 mL) and methanol (0.6 mL)) A solution of 3-fluoroazetidine-1-yl) pyridin-2-yl) formamide] -2-ethylbutanoate (160 mg, 0.29 mmol) was degassed for 10 minutes. Pd-C (10%, 80 mg) was added and degassing was continued for another 2 minutes. The mixture was placed under a hydrogen atmosphere at balloon pressure and stirred at 25 ° C. for 17 hours. The reaction mixture is filtered through a Celite bed and concentrated in vacuo to crude (rac) -trans-3-fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6. -{[-2- (Hydroxymethyl) cyclopropyl] methoxy} pyridin-2-yl] formamide} butanoate (140 mg) was obtained as a colorless gum. Preparative chiral HPLC (column: Chilarpak IC (250 x 4.6 mm), 5i; mobile phase: hexane / EtOH / isopropylamine: 80/20 / 0.1; flow velocity: 1.0 mL / min) The title compound (37 mg, 26%) was obtained as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity was 98.46%, holding time = 3.28 minutes, MS calculated value: 469, MS measured value: 470.1 [M + H ⁺ ].

Example 31
(Rac) -trans-3-fluoropropyl 2-ethyl-2-[[6-[[-2- (hydroxymethyl) cyclopropyl] methoxy] -5- [3- (p-tolylsulfonyloxy) azetidine-1 -Il] Pyridine-2-carbonyl] Amino] Butanoart

密封管中、ＤＣＭ（５mL）中の（rac）−trans−３−フルオロプロピル ２−［（６−｛［−２−［（ベンジルオキシ）メチル］シクロプロピル］メトキシ｝−５−（３−ヒドロキシアゼチジン−１−イル）ピリジン−２−イル）ホルムアミド］−２−エチルブタノアート（実施例２２ｅ、２２５mg、０．４０mmol）の溶液に、２，６−ルチジン（０．２５mL、２．０２mmol）及び塩化トシル（２３０mg、１．２１mmol）を加えた。反応混合物を５０℃で１６時間撹拌し、ＤＣＭ（２０mL）で希釈し、そして１Ｎ ＨＣｌ水溶液及び水（１０mL）で洗浄した。有機層を乾燥し、濾過し、そして真空中で濃縮した。粗生成物を分取ＨＰＬＣにより精製して、標記化合物を帯黄色固体として得た（１６mg、６％）。 a) (Rac) -trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-{[(4-methylbenzene) sulfonyl) ] Oxy} azetidine-1-yl) pyridin-2-yl) formamide] -2-ethylbutanoate

(Rac) -trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-hydroxy) in a sealed tube, DCM (5 mL) Azetidine-1-yl) pyridin-2-yl) formamide] -2-ethylbutanoate (Example 22e, 225 mg, 0.40 mmol) in a solution of 2,6-lutidine (0.25 mL, 2.02 mmol). ) And tosyl chloride (230 mg, 1.21 mmol) were added. The reaction mixture was stirred at 50 ° C. for 16 hours, diluted with DCM (20 mL) and washed with 1N aqueous HCl and water (10 mL). The organic layer was dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound as a yellowish solid (16 mg, 6%).

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). Purity: crude material, retention time = 2.44 minutes, MS calculated value: 711, MS measured value: 712.5 [M + H ⁺ ].

b) (Rac) -trans-3-fluoropropyl 2-ethyl-2-[[6-[[-2- (hydroxymethyl) cyclopropyl] methoxy] -5- [3- (p-tolylsulfonyloxy) azetidine -1-Il] pyridin-2-carbonyl] amino] butanoate (rac) -trans-3-fluoropropyl 2-[(6-{[-2-[(benzyloxy) methyl] cyclopropyl) in EtOAc (2 mL)) ] Methoxy} -5- (3-{[(4-methylbenzene) sulfonyl] oxy} azetidine-1-yl) pyridin-2-yl) formamide] -2-ethylbutanoate (16.0 mg, 0.02 mmol) ) Was degassed. Pd / C (10 wt%, 8.0 mg) was added. The mixture was degassed, placed H _2, and stirred 16 h at ambient temperature. The mixture was filtered through Celite and the Celite bed was washed with EtOAc. The filtrate was _{dried over anhydrous Na 2} SO ₄ , filtered and concentrated in vacuo to produce the title compound (10.1 mg, 72%) as a colorless sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 89.55%, holding time = 3.53 minutes, MS calculated value: 621, MS measured value: 622.2 [M + H ⁺ ].

Example 32
3-Fluoropropyl 2-[[6-[[(1S, 2S) -2- (benzyloxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino] -2-ethyl-butanoart

a) 2-[(6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-yl) Formamide] -2-ethylbutanoic acid

3-Fluoropropyl 2-ethyl-2-[(6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine) in DMF (1.0 mL)) Benzyl bromide (7 mg, 0.04 mmol) was added to a solution of -1-yl) pyridin-2-yl) formamide] butanoate (Example 15 m, 20 mg, 0.04 mmol). The mixture was cooled to 0 ° C. and placed in an argon atmosphere. Sodium hydride (3 mg, 0.08 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 hours, poured into water (10 mL), acidified with aqueous HCl and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried, filtered and concentrated in vacuo to give the title compound (20 mg, 94%) as a yellow sticky mass.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 84.14%, holding time = 0.54 minutes, MS calculated value: 511, MS measured value: 512.0 [M + H ⁺ ].

b) 3-Fluoropropyl 2-[[6-[[(1S, 2S) -2- (benzyloxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino] -2-ethyl-butanoate 2-[(6-{[(1S, 2S) -2-[(benzyloxy) methyl] cyclopropyl] methoxy} -5-(in DMF (1.0 mL)) 3-methoxy-1-yl) pyridin-2-yl) formamide] -2-ethylbutanoic acid (20 mg, to a solution of _{0.04mmol), K 2 CO 3 (} 16mg, 0.12mmol) and 1-iodo - 3-Fluoro-propane (22 mg, 0.12 mmol) was added. The reaction mixture was stirred at 25 ° C. for 2 hours, poured into water, quenched with 1N aqueous HCl and extracted with EtOAc (3 x 15 mL). The combined extracts were washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by preparative TLC (20% EtOAc in hexanes) to give the title compound (11 mg, 49%) as a colorless liquid.

LCMS: Column Zorbax Ext C 18 (50 x 4.6 mm), 5 μ, (Mobile phase: 1.5 minutes, 90% [10 mM NH ₄ OAc in water] and 10% [CH ₃ CN] to 70% [10 mM in water] The mobile phase composition was retained in NH ₄ OAc] and 30% [CH ₃ CN] for an additional 3.0 minutes and in 10% [10 mM NH ₄ OAc in water] and 90% [CH ₃ CN] for up to 4 minutes. Finally, it returned to the initial condition in 5 minutes). The purity is 98.02%, holding time = 4.07 minutes, MS calculated value: 571, MS measured value: 572.1 [M + H ⁺ ].

Example 33
Fluoromethyl 2-ethyl-2-[[6-[[3- (hydroxymethyl) oxetane-3-yl] methoxy] -5-pyrrolidin-1-yl-pyridin-2-carbonyl] amino] butanoate

２５０mLの３口フラスコ中で、５−ブロモ−６−クロロピコリン酸（ＣＡＮ ９５９９５８−２５−９、１．８ｇ、７．６１mmol、当量：１）を、ＤＭＦ（１００mL）と合わせて、無色の溶液を得た。混合物を０℃に冷却し、水素化ナトリウム（９１３mg、２２．８mmol、当量：３）を加えた。反応混合物を０℃で２０分間撹拌した。１０mLの丸底フラスコ中で、（３−（（ベンジルオキシ）メチル）オキセタン−３−イル）メタノール（ＣＡＮ １４２７３１−８４−８、２．０６ｇ、９．９mmol、当量：１．３）を、ＤＭＦ（１０mL）と合わせて、無色の溶液を得、これを反応混合物にゆっくりと加えた。反応混合物を８０℃に４時間加熱し、周囲温度まで冷やした。ヨウ化メチル（３．２４ｇ、１．４３mL、２２．８mmol、当量：３）を加え、撹拌を１８時間続けた。溶媒を減圧下で除去した。残留物をＥｔＯＡｃ（１００mL）及び水（１００mL）で希釈した。層を分離し、水相をＥｔＯＡｃ（２×４０mL）で抽出した。合わせた有機層をブライン（１×１００mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥し、濾過し、そして減圧下で乾燥させた。粗生成物を、カラムクロマトグラフィー（ＳｉＯ_２、５０ｇ、ｈｅｐｔ．／ＥｔＯＡｃ）により精製して、標記化合物（２．８２ｇ、８８％）を無色の油状物として得た、ＭＳ（ＩＳＰ）：４２４．１２１ ［ＭＨ^＋］。 a) Methyl 6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5-bromopicolinate

A colorless solution of 5-bromo-6-chloropicolinic acid (CAN 959958-25-9, 1.8 g, 7.61 mmol, equivalent: 1) in a 250 mL three-necked flask combined with DMF (100 mL). Got The mixture was cooled to 0 ° C. and sodium hydride (913 mg, 22.8 mmol, eq: 3) was added. The reaction mixture was stirred at 0 ° C. for 20 minutes. In a 10 mL round bottom flask, (3-((benzyloxy) methyl) oxetane-3-yl) methanol (CAN 142731-84-8, 2.06 g, 9.9 mmol, equivalent: 1.3) was added to DMF. Combined with (10 mL), a colorless solution was obtained, which was added slowly to the reaction mixture. The reaction mixture was heated to 80 ° C. for 4 hours and cooled to ambient temperature. Methyl iodide (3.24 g, 1.43 mL, 22.8 mmol, equivalent: 3) was added and stirring was continued for 18 hours. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over Na ₂ SO ₄ , filtered and dried under reduced pressure. The crude product was purified by column chromatography (SiO ₂ , 50 g, hept./ EtOAc) to give the title compound (2.82 g, 88%) as a colorless oil, MS (ISP): 424. 121 [MH ⁺ ].

実施例１ｃに記載した手順と同様にして、メチル ６−（（３−（（ベンジルオキシ）メチル）オキセタン−３−イル）メトキシ）−５−ブロモピコリナートを、ピロリジンと反応させて、標記化合物を淡褐色の油状物として得た、ＭＳ（ＩＳＰ）：４１３．３６５ ［ＭＨ^＋］。 b) Methyl 6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picolinate

Methyl 6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5-bromopicolinate is reacted with pyrrolidine in the same manner as in Example 1c to give the title compound. Was obtained as a light brown oil, MS (ISP): 413.365 [MH ⁺ ].

実施例１１ａに記載した手順と同様にして、メチル ６−（（３−（（ベンジルオキシ）メチル）オキセタン−３−イル）メトキシ）−５−（ピロリジン−１−イル）ピコリナートを、ＫＯＨで加水分解して、標記化合物を白色の固体として得、これを更に精製することなく次の反応工程で用いた、ＭＳ（ＩＳＰ）：３９９．３０５ ［ＭＨ^＋］。 c) 6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picolinic acid

Methyl 6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picolinate was hydrolyzed with KOH in the same manner as in Example 11a. Decomposition to give the title compound as a white solid, which was used in the next reaction step without further purification, MS (ISP): 399.305 [MH ⁺ ].

２５mlの丸底フラスコ中で、６−（（３−（（ベンジルオキシ）メチル）オキセタン−３−イル）メトキシ）−５−（ピロリジン−１−イル）ピコリン酸（６６０mg、１．６６mmol、当量：１）を、ＤＭＦ（１０mL）と合わせて、淡黄色の溶液を得た。ＴＢＴＵ（５３２mg、１．６６mmol、当量：１）及びＤＩＰＥＡ（８５６mg、１．１６mL、６．６３mmol、当量：４）を加えた。エチル ２−アミノ−２−エチルブタノアート塩酸塩（ＣＡＮ １１３５２１９−２９−２、３８９mg、１．９９mmol、当量：１．２）を加え、反応混合物を周囲温度で１７時間撹拌した。更なる０．１２当量のエチル ２−アミノ−２−エチルブタノアート塩酸塩及び０．１当量のＴＢＴＵを加え、撹拌を２時間続けた。反応混合物をＥｔＯＡｃで希釈し、飽和ＮａＨＣＯ_３（３×２５mL）、１Ｍ ＨＣｌ（３×２５mL）及び飽和ＮａＣｌ（１×２５mL）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、真空中で濃縮した。粗生成物を、カラムクロマトグラフィー（ＳｉＯ_２、５０ｇ、ｈｅｐｔ．／ＥｔＯＡｃ）により精製して、標記化合物（５８７mg、６６％）を無色の油状物として得た、ＭＳ（ＩＳＰ）：５４０．４３２ ［ＭＨ^＋］。 d) Ethyl 2-(6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) -2-ethylbutanoate

In a 25 ml round bottom flask, 6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picolinic acid (660 mg, 1.66 mmol, equivalent: 1) was combined with DMF (10 mL) to give a pale yellow solution. TBTU (532 mg, 1.66 mmol, equivalent: 1) and DIPEA (856 mg, 1.16 mL, 6.63 mmol, equivalent: 4) were added. Ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2, 389 mg, 1.99 mmol, equivalent: 1.2) was added and the reaction mixture was stirred at ambient temperature for 17 hours. An additional 0.12 equivalent of ethyl 2-amino-2-ethylbutanoate hydrochloride and 0.1 equivalent of TBTU were added and stirring was continued for 2 hours. The reaction mixture was diluted with EtOAc _{and washed with saturated NaCl 3} (3 x 25 mL), 1M HCl (3 x 25 mL) and saturated NaCl (1 x 25 mL). The organic layer was _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , 50 g, hept./ EtOAc) to give the title compound (587 mg, 66%) as a colorless oil, MS (ISP): 540.432 [. MH ⁺ ].

２５mlの丸底フラスコ中で、エチル ２−（６−（（３−（（ベンジルオキシ）メチル）オキセタン−３−イル）メトキシ）−５−（ピロリジン−１−イル）ピコリンアミド）−２−エチルブタノアート（５５６mg、１．０３mmol、当量：１）を、酢酸エチル （５mL）及びＭｅＯＨ（５mL）と合わせて、無色の溶液を得た。Ｐｄ／Ｃ（２５０mg、２３５μmol、当量：０．２２８）を加え、反応混合物を水素ガス雰囲気下で４４時間撹拌した。別の部分のＰｄ／Ｃ（２００mg）を加え、撹拌を水素ガス雰囲気下で１６時間続けた。混合物をセライトで濾過し、有機溶媒を減圧下で除去して、標記化合物（３７０mg、８０％）を白色の固体として得た、ＭＳ（ＩＳＰ）：４５０．３９６ ［ＭＨ^＋］。 e) Ethyl 2-ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate

Ethyl 2-(6-((3-((benzyloxy) methyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) -2-ethyl in a 25 ml round bottom flask Butanoate (556 mg, 1.03 mmol, equivalent: 1) was combined with ethyl acetate (5 mL) and MeOH (5 mL) to give a colorless solution. Pd / C (250 mg, 235 μmol, equivalent: 0.228) was added and the reaction mixture was stirred under a hydrogen gas atmosphere for 44 hours. Another portion of Pd / C (200 mg) was added and stirring was continued for 16 hours in a hydrogen gas atmosphere. The mixture was filtered through Celite and the organic solvent was removed under reduced pressure to give the title compound (370 mg, 80%) as a white solid, MS (ISP): 450.396 [MH ⁺ ].

実施例１１ａに記載した手順と同様にして、エチル ２−エチル−２−（６−（（３−（ヒドロキシメチル）オキセタン−３−イル）メトキシ）−５−（ピロリジン−１−イル）ピコリンアミド）ブタノアートを、ＫＯＨで加水分解して、標記化合物を褐色の油状物として得、これを更に精製することなく次の反応工程で用いた。 f) 2-Ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoic acid

Ethyl 2-ethyl-2- (6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picolinamide, similar to the procedure described in Example 11a. ) Butanoate was hydrolyzed with KOH to give the title compound as a brown oil, which was used in the next reaction step without further purification.

g) Fluoromethyl 2-ethyl-2-[[6-[[3- (hydroxymethyl) oxetane-3-yl] methoxy] -5-pyrrolidin-1-yl-pyridin-2-carbonyl] amino] Butanoart Example 2-Ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picolinamide) butanoic acid in the same manner as described in 11b. Was reacted with fluoro-iodo-methane to give the title compound as a colorless oil, MS (ESI): 454.4 [MH ⁺ ].

実施例１１ｂに記載した手順と同様にして、２−エチル−２−（６−（（３−（ヒドロキシメチル）オキセタン−３−イル）メトキシ）−５−（ピロリジン−１−イル）ピコリンアミド）ブタン酸（実施例３３ｆ）を、１−フルオロ−２−ヨードエタンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＥＳＩ）：４６８．４ ［ＭＨ^＋］。 Example 34
2-Fluoroethyl 2-Ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate

2-Ethyl-2- (6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picolinamide) in the same manner as in Example 11b. Butanoic acid (Example 33f) was reacted with 1-fluoro-2-iodoethane to give the title compound as a colorless oil, MS (ESI): 468.4 [MH ⁺ ].

実施例１１ｂに記載した手順と同様にして、２−エチル−２−（６−（（３−（ヒドロキシメチル）オキセタン−３−イル）メトキシ）−５−（ピロリジン−１−イル）ピコリンアミド）ブタン酸（実施例３３ｆ）を、１−ヨード−３−フルオロプロパンと反応させて、標記化合物を無色の油状物として得た、ＭＳ（ＥＳＩ）：４８２．４ ［ＭＨ^＋］。 Example 35
3-Fluoropropyl 2-ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate

2-Ethyl-2- (6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) in the same manner as in Example 11b. Butanoic acid (Example 33f) was reacted with 1-iodo-3-fluoropropane to give the title compound as a colorless oil, MS (ESI): 482.4 [MH ⁺ ].

Example 36
Pharmacological test The following test was performed to measure the activity of the compound of formula I.

Radioligand binding assay Using the recommended amount of human fetal kidney (HEK) cell expression membrane preparation (PerkinElmer) expressing the human CNR1 or CNR2 receptor, as the radioligand, 1.5 or 2. The affinity of the compound of the present invention for the cannabinoid CB1 receptor was determined in combination with 6 nM [3H] -CP-55,940 (Perkin Elmer). A total volume of 0.2 mL of binding buffer (50 mM Tris, 5 mM MgCl2, 2.5 mM EDTA for CB1 receptors, and 0.5% (wt / vol) fatty acid-free BSA, pH 7.4, and CB2 receptors In the case of, the bond was carried out by shaking at 30 ° C. for 1 hour in 50 mM Tris, 5 mM MgCl2, 2.5 mM EGTA, and 0.1% (wt / vol) fatty acid-free BSA, pH 7.4). The reaction was stopped by rapid filtration through a microfiltration plate (UniFilter GF / B filter plate; Packard) coated with 0.5% polyethyleneimine. Non-linear regression analysis (Activity Base, ID Business Solution, Limited) was used to analyze the bound radioactivity Ki, and the Kd value of [3H] CP55,940 was determined from the saturation experiment. The compound of formula (I) exhibits excellent affinity for the CB2 receptor.

The compound according to formula (I) has an activity (Ki) of 0.5 nM to 10 μM in the above assay. The compound of the particular formula (I) has an activity (Ki) of 0.5 nM to 3 μM in the above assay. Other specific formula (I) compounds have activity (Ki) in the above assay of 0.5 nM-100 nM.

17-24 hours prior to the cAMP assay experiment, in DMEM (Invitrogen No. 31331) containing 10% fetal bovine serum from a clear flat-bottomed black 96-well plate (Corning Costar # 3904) and supplemented with 1 × HT. CHO cells expressing the human CB1 or CB2 receptor are seeded at 50,000 cells / well and incubated in a humidified incubator at 5% CO2, 37 ° C. Growth medium was replaced with Krebs Ringer bicarbonate buffer containing 1 mM IBMX and incubated at 30 ° C. for 30 minutes. Compounds were added until the final assay volume reached 100 μL and incubated at 30 ° C. for 30 minutes. Using the cAMP-Nano-TRF detection kit (Roche Diagnostics), 50 μL of lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN ₃ ) and detection solution (20 μM mAb Alexa700- The assay was stopped by adding 50 μL of cAMP 1: 1 and 48 μM ruthenium-2-AHA-cAMP) and shaken at room temperature for 2 hours. The time-resolved energy transition is measured by a TRF reader (Evotec Technologies GmbH) equipped with an ND: YAG laser as an excitation source. The plate is measured twice at 730 (bandwidth 30 nm) or 645 nm (bandwidth 75 nm) with a total irradiation time of 10 seconds for excitation at 355 nm and emission at delay 100 ns and gate 100 ns, respectively. The FRET signal is calculated as follows: FRET = T730-Alexa730-P (T645-B645) (where P = Ru730-B730 / Ru645-B645, where T730 is in the test well measured at 730 nM. Yes, T645 is a test well measured at 645 nm, and B730 and B645 are buffer controls at 730 nm and 645 nm, respectively). The cAMP content is determined from a function of the standard curve ranging from 10 μM to 0.13 nM cAMP.

Activity Base analysis (ID Business Solution, Limited) with a calculated _{EC 50} values. The EC ₅₀ values of the broad cannabinoid agonist obtained for reference compound from this assay were consistent with value published in the scientific literature.

In the above assay, the compounds of the present invention has a human CB2 _{EC 50} is 0.5NM～10myuM. Compounds in accordance with certain of the present invention has a human CB2 _{EC 50} is 0.5NM～1myuM. A further specific compound according to the invention has a human CB2 EC ₅₀ which is 0.5 nM to 100 nM. The compound exhibits at least 10-fold selectivity for the human CB1 receptor in both the radioligand and cAMP assays, or in one of these two assays.

The results obtained for the representative compounds of the present invention are shown in the table below.

Example A
A film-coated tablet containing the following components can be produced as before.

The active ingredient is sieved and mixed with microcrystalline cellulose, and the mixture is granulated with aqueous polyvinylpyrrolidone solution. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to produce 120 or 350 mg kernels, respectively. The nucleus is lacquered with the aqueous / aqueous dispersion of the film coating described above.

Example B
Capsules containing the following components can be produced as before.

Ingredients are sieved, mixed and filled into size 2 capsules.

Example C
The injection solution may have the following composition.

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (partial). Adjust the pH to 5.0 by adding acetic acid. Adjust the volume to 1.0 mL by adding the remaining amount of water. The solution is filtered, filled into vials with the appropriate overage, and sterilized.

Claims (23)

Compound of formula (I)

(During the ceremony,
A ¹ is -CH- or nitrogen;
A ² is -CH _2- or carbonyl;
R ¹ is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, haloalkoxyalkyl, hydroxyalkylcycloalkyl, oxetanyl, haloalkoxyalkyloxetanyl, hydroxyalkyloxetanyl, haloalkyloxetanyl, 1-fluoroethyl, 1-fluoro-propa-2- Il, fluoro-tert-butyl, cyclopropylfluoromethyl, fluorocyclopropyl, haloxanyl, halotetrahydrofuranyl, phenylalkoxyalkylcycloalkyl, 1-fluoro-1,1-dijuteropropa-2-yl, fluorodijutero Methyl, Fluorodiuteromethyloxyalkyl Cycloalkyl, 2-Fluoro-2,2-Dijuteroethyloxyalkylcycloalkyl, Fluorodiuteromethylcycloalkyl, Fluorodiuteromethyloxyalkyl, Fluorodiuteromethyl Alkyl, fluorodijuteromethyloxyalkyl oxetanyl, 2-fluoro-2,2-dijuteroethyloxyalkyl oxetanyl, 3-fluoro-3,3-dijuteropropyloxyalkyl oxetanyl, or fluorodijuteromethyloxetanyl Is;
R ² is alkoxy azetidinyloxyimino, Haroazechijiniru, dihalo azetidinyloxyimino, pyrrolidinyl, or an alkyl phenylsulfonyloxy azetidinyloxyimino;
R ³ and R ⁴ are independently selected from hydrogen, alkyl, alkenyl, and juterioalkyl;
R ⁵ is hydrogen, alkyl, haloalkyl, Jewelery Theriault alkyl, alkylphenyl sulfonyloxy alkyl, alkylphenyl sulfonyloxy Jewelery Theriault alkyl, or a hydroxyalkyl; and,
X is oxygen or -NH-)
Or its pharmaceutically acceptable salt. The compound according to claim 1, wherein A ^{1 is −CH−.} The compound according to claim 1 or 2, wherein A ^{2 is a carbonyl.} The compound according to any one of claims 1 to 3, wherein R ^{1 is haloalkoxyalkylcycloalkyl, haloalkylcycloalkyl, or hydroxyalkylcycloalkyl.} The compound according to any one of claims 1 to 4, wherein R ^{1 is fluoromethoxymethylcyclopropyl, fluoromethylcyclopropyl, or hydroxymethylcyclopropyl.} R ² is alkoxy azetidinyloxyimino or Haroazechijiniru compound of any one of claims 1-5. R ² is methoxy azetidinyloxyimino or fluoro azetidinyloxyimino compound of any one of claims 1-6. The compound according to any one of claims 1 to 7, wherein R ³ and R ⁴ are both alkyl at the same time, or both are juuterioalkyl at the same time. The compound according to any one of claims 1 to 8, wherein R ³ and R ⁴ are both ethyl at the same time or both are juuterioethyl at the same time. The compound according to any one of claims 1 to 9, wherein R ^{5 is alkyl, haloalkyl, or halojuuterioalkyl.} R ⁵ is ethyl, fluoromethyl, fluoropropyl, fluorobutyl, or fluoro hexadeuteriodimethylsulfoxide Theriault propyl The compound of any one of claims 1 to 10. The compound according to any one of claims 1 to 9, wherein X is oxygen. Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} butanoate and ethyl 2-ethyl-2-{[6-{[(1R, R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} butanoate and ethyl 2-ethyl-2-{[6-{[(1S, 2R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-({6- [3- (fluoromethoxy) -2,2-dimethylpropoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
(+)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart;
(-)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoateethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine) -1-yl) pyridin-2-carbonyl] amino} butanoate;
(-)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carbonyl] amino} butanoate;
(+)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
(+)-Trans-2-fluoroethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart;
(-)-Trans-2-fluoroethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine- 2-carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3) -Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
Fluoromethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
2-Fluoroethyl 2-Ethyl-2-{[6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3) -Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -6-{[(1R, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
Fluoromethyl 2-ethyl-2-({5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carbonyl} amino) butanoate;
2-Fluoroethyl 2-Ethyl-2-({5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carbonyl} amino) butanoate;
3-Fluoropropyl 2-ethyl-2-({5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carbonyl} amino) butanoate;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2- Carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine- 2-Carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine- 2-Carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine -2-Carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy ] Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy ] Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) Methoxy] Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) Methoxy] Pyridine-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridin-2-carboxamide ;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine-2 -Carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -5- (3-methoxyazetidine-1-yl) -6-[(oxetane-3-yl) methoxy] pyridine-2 -Carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-[(oxetane-3-yl) methoxy] -5- (pyrrolidin-1-yl) pyridine- 2-Carboxamide;
Ethyl 2-ethyl-2-{[6-({3-[(fluoromethoxy) methyl] oxetane-3-yl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-({3-[(2-fluoroethoxy) methyl] oxetane-3-yl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({3-[(3-fluoropropoxy) methyl] oxetane-3-yl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
Fluoromethyl 2-ethyl-2-{[6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} Butano art;
2-Fluoroethyl 2-Ethyl-2-{[6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
N-[(2S) -1- (fluoromethoxy) propan-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) Il) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) propan-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) propan-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -3-methylbutano-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -3-methylbutano-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -3-methylbutano-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (fluoromethoxy) -4-methylpentane-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazeti) Din-1-yl) Pyridine-2-carboxamide;
N-[(2S) -1- (2-fluoroethoxy) -4-methylpentane-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N-[(2S) -1- (3-fluoropropoxy) -4-methylpentane-2-yl] -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
N- {3-[(fluoromethoxy) methyl] pentane-3-yl} -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carboxamide;
N- {3-[(2-fluoroethoxy) methyl] pentane-3-yl} -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
N- {3-[(3-Fluoropropoxy) methyl] pentane-3-yl} -6-{[3- (hydroxymethyl) oxetane-3-yl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3) -Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-({(1S, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-({(1S, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-{[(1S, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-methoxyazeti) Gin-1-yl) Pyridine-2-carboxamide;
6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5- (3- (3-) Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-({(1R, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-({(1R, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5-( 3-Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5- (3-methoxyazetidine) -1-yl) Pyridine-2-carboxamide;
6-({3-[(fluoromethoxy) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine-1-) Il) Pyridine-2-carboxamide;
6-({3-[(2-fluoroethoxy) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
6-({3-[(3-Fluoropropoxy) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine- 1-yl) Pyridine-2-carboxamide;
6-{[3- (fluoromethyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine-1-yl) pyridine -2-Carboxamide;
6-({3-[(fluoromethoxy) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carboxamide;
6-({3-[(2-fluoroethoxy) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
6-({3-[(3-Fluoropropoxy) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carboxamide;
6-{[3- (fluoromethyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1-yl) pyridine- 2-Carboxamide;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyrazine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyrazine-2 −carbonyl] amino} butanoart;
6-({(1S, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-4-methylpentane-2-yl] -5- (3-Methoxyazetidine-1-yl) pyrazine-2-carboxamide;
6-({(1R, 2S) -2-[(3-fluoropropoxy) methyl] cyclopropyl} methoxy) -N-[(2S) -1-hydroxy-3-methylbutano-2-yl] -5-( 3-Methoxyazetidine-1-yl) pyrazine-2-carboxamide;
Ethyl 2-ethyl-2-({6-[(3-fluorooxane-4-yl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
1,4-Anhydro-2,3-dideoxy-5-O- [6-{[3- (ethoxycarbonyl) pentane-3-yl] carbamoyl} -3- (3-methoxyazetidine-1-yl) pyridine -2-yl] -2-fluoropentitol;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[2-fluoro (2,2-dijuuterio) ethyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate ;
Ethyl 2-ethyl-2-({6-[(3-fluorooxane-4-yl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
1,4-Anhydro-2,3-dideoxy-5-O- [6-{[3- (ethoxycarbonyl) pentane-3-yl] carbamoyl} -3- (3-methoxyazetidine-1-yl) pyridine -2-yl] -2-fluoropentitol;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2-({[2-fluoro (2,2-2-2H_2_) ethyl] oxy} methyl) cyclopropyl] methoxy} -5 -(3-Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2- [fluoro (dijuuterio) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2- [fluoro (dijuuterio) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2-({[2-fluoro (2,2-dijuuterio) ethyl] oxy} methyl) cyclopropyl] methoxy} -5- (3) -Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6-(3-{[fluoro (dijuuterio) methyl] oxy} -2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2,2-dimethyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2S) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2R) -2-({[fluoro (dijuuterio) methyl] oxy} methyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[2-fluoro (2,2-dijuuterio) ethyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate ;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[2-fluoro (2,2-dijuuterio) ethyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate ;
Ethyl 2-ethyl-2-{[6-{[3-fluoro-2-methyl (3,3-dijuuterio) propyl] oxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl ] Amino} Butanoart;
6-{[3-({[fluoro (dijuuterio) methyl] oxy} methyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3- (3-) Methoxyazetidine-1-yl) Pyridine-2-carboxamide;
6-{[3-({[2-fluoro (2,2-dijuuterio) ethyl] oxy} methyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-{[3-({[3-Fluoro (3,3-dijuuterio) propyl] oxy} methyl) oxetane-3-yl] methoxy} -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-({3- [fluoro (dijuuterio) methyl] oxetane-3-yl} methoxy) -N-[(2S) -1-hydroxypropan-2-yl] -5- (3-methoxyazetidine-1-yl) Il) Pyridine-2-carboxamide;
6-{[3-({[fluoro (dijuuterio) methyl] oxy} methyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxy Azetidine-1-yl) Pyridine-2-carboxamide;
6-{[3-({[2-fluoro (2,2-dijuuterio) ethyl] oxy} methyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl]- 5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-{[3-({[3-Fluoro (3,3-dijuuterio) propyl] oxy} methyl) oxetane-3-yl] methoxy} -N- [3- (hydroxymethyl) pentane-3-yl]- 5- (3-Methoxyazetidine-1-yl) pyridin-2-carboxamide;
6-({3- [fluoro (dijuuterio) methyl] oxetane-3-yl} methoxy) -N- [3- (hydroxymethyl) pentane-3-yl] -5- (3-methoxyazetidine-1-yl) ) Pyridine-2-carboxamide;
3-Fluoropropyl 3,4-dijuuterio-2- (1,2-dijuuterioethyl) -2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5] -(3-Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
Fluoromethyl 2-ethyl-2- (6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate;
2-Fluoroethyl 2-Ethyl-2- (6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate;
3-Fluoropropyl 2-ethyl-2-(6-((3- (hydroxymethyl) oxetane-3-yl) methoxy) -5- (pyrrolidin-1-yl) picoline amide) butanoate;
(1,1,2,2,3,3-Hexajuterio-3-fluoro-propyl) 2-Ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl]] Methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
3-Fluoropropyl 2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino ] -2-Vinyl-Buta-3-Enoart;
3-Fluoropropyl 3,4-dijuuterio-2- (1,2-dijuuterioethyl) -2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5] -(3-Methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
(Rac) -trans-3-fluoropropyl 2-[[6-[[(1S, 2S) -2- (benzyloxymethyl) cyclopropyl] methoxy] -5- (3-hydroxyazetidine-1-yl) Pyridine-2-carbonyl] amino] -2-ethyl-butanoate;
3- (p-Tolylsulfonyloxy) propyl 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1) -Il) Pyridine-2-carbonyl] Amino] Butanoart;
[1,1,2,2,3,3-hexajuuterio-3- (p-tolylsulfonyloxy) propyl] 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxy) Methyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino] butanoate;
4-Fluorobutyl 2-ethyl-2-[[6-[[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino] butanoart;
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -6-[[(1S, 2S) -2- (hydroxymethyl) cyclo Propyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridine-2-carboxamide;
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6- [ [(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridine-2-carboxamide;
N- [1-ethyl-1-[[(1S) -1- (hydroxymethyl) -3-methyl-butyl] carbamoyl] propyl] -5- (3-fluoroazetidine-1-yl) -6- [ [(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy] pyridine-2-carboxamide;
3-Fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} pyridine-2 -Il] formamide} butanoart;
3-Fluoropropyl 2-ethyl-2-{[5- (3-fluoroazetidine-1-yl) -6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} pyridine-2 -Il] formamide} butanoart;
(Rac) -trans-3-fluoropropyl 2-ethyl-2-[[6-[[-2- (hydroxymethyl) cyclopropyl] methoxy] -5- [3- (p-tolylsulfonyloxy) azetidine-1 -Il] Pyridine-2-carbonyl] Amino] Butanoart;
3-Fluoropropyl 2-[[6-[[(1S, 2S) -2- (benzyloxymethyl) cyclopropyl] methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino] -2-ethyl-butanoart;
Ethyl 2-ethyl-2-{[6- (2-fluoropropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2,2-dimethylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-({6-[(1-fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
Ethyl 2-ethyl-2-({6-[(2-fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
Ethyl 2-ethyl-2-{[6- (2-fluoropropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6- (3-fluoro-2-methylpropoxy) -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-({6-[(1-fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate; and ethyl 2-ethyl -2-({6-[(2-Fluorocyclopropyl) methoxy] -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl} amino) butanoate;
The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is selected from the above. Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino} butanoate and ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-) 1-yl) pyridine-2-carbonyl] amino} butanoate;
Ethyl 2-ethyl-2-{[6-({(1S, 2S) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2R) -2-[(2-fluoroethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine -2-carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-{[(1R, 2S) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-{[(1S, 2R) -2- (fluoromethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2-carbonyl] Amino} Butanoart;
Ethyl 2-ethyl-2-{[6-({(1R, 2S) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
Ethyl 2-ethyl-2-{[6-({(1S, 2R) -2-[(fluoromethoxy) methyl] cyclopropyl} methoxy) -5- (3-methoxyazetidine-1-yl) pyridine-2 −carbonyl] amino} butanoart;
(+)-Trans-Ethyl 2-Ethyl-2-{[6-({-2-[(fluoromethoxy) Methyl] Cyclopropyl} methoxy) -5- (3-Methoxyazetidine-1-yl) Pyridine- 2-carbonyl] amino} butanoart;
(+)-Trans-Fluoromethyl 2-ethyl-2-{[6-{[-2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridin-2- Carbonyl] amino} butanoart;
3-Fluoropropyl 2-ethyl-2-{[6-{[(1S, 2S) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine-1-yl) pyridine-2 -Carbonyl] amino} butanoate; and 3-fluoropropyl 2-ethyl-2-{[6-{[(1R, 2R) -2- (hydroxymethyl) cyclopropyl] methoxy} -5- (3-methoxyazetidine) -1-yl) pyridine-2-carbonyl] amino} butanoate;
The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which is selected from the above. A process for preparing the compound according to any one of claims 1 to 14, which comprises one of the following steps:
(A) Compound of formula (A1) in the presence of coupling agent and base

And the compound of formula (A2)

Reaction with;
^{(B) R} 2 M, in the presence of a palladium catalyst, and a base, compounds of formula (B)

reaction;
(In these equations, A ¹ , A ² , R ^{1 to} R ⁵ , and X are as defined in any one of claims 1 to 12, and Y is a halogen). The compound according to any one of claims 1 to 14, when produced according to the process according to claim 15. The compound according to any one of claims 1 to 14, for use as a therapeutically active substance. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 and a therapeutically inert carrier. Pain, atherosclerosis, age-related yellow spot degeneration, diabetic nephropathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, myocardial disease, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening Claims 1-14 for treating or preventing sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation. Use of the compound according to any one item. Pain, atherosclerosis, age-related yellow spot degeneration, diabetic retinopathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, myocardiology, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening To prepare a drug for treating or preventing sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation. Use of the compound according to any one of claims 1 to 14. Pain, atherosclerosis, age-related yellow spot degeneration, diabetic nephropathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, myocardial disease, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening Claims 1 to be used in the treatment or prevention of sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation. The compound according to any one of 14. Pain, atherosclerosis, age-related yellow spot degeneration, diabetic retinopathy, glaucoma, diabetes, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, pulmonary fibrosis, kidney Fibrosis, systemic fibrosis, acute transplant rejection, chronic transplant nephropathy, diabetic nephropathy, glomerular nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, burns, burns, thickening A method for treating or preventing sex scars, keloids, gingival fever, liver cirrhosis or tumors, bone mass control, neurodegeneration, attacks, transient cerebral ischemic attacks, or diabetic inflammation, effective amounts. A method comprising administering a compound as defined in any one of claims 1-14 to a patient in need thereof. The invention described herein.